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BIOLOGICAL MACROMOLECULES
 BIOLOGICAL
MACROMOLECULES
BIOACTIVITY AND BIOMEDICAL
APPLICATIONS

Edited by

Amit Kumar Nayak

Department of Pharmaceutics, Seemanta Institute of Pharmaceutical Sciences, Jharpokharia, India

Amal Kumar Dhara

Department of Pharmacy, Contai Polytechnic, Contai, India

Dilipkumar Pal
Department of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central University),
Bilaspur, India
Academic Press is an imprint of Elsevier
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Typeset by MPS Limited, Chennai, India
 Contents

List of contributors xiii 2.2.2 Lysostaphin 28

2.2.3 Metallo-β-lactamase-like lactonase 32
Preface xix 2.3 Chitosan as a bioactive polysaccharide 36
2.3.1 Relationship of chitosan physicochemical
property and its bioactivity 37
I 2.3.2 Bioactivity of chitosan with modified
Background functional group 41
2.4 Conclusion 43
References 43
1. Biological macromolecules: sources,
properties, and functions 3. The importance of biological
AMAL KUMAR DHARA AND AMIT KUMAR NAYAK macromolecules in biomedicine
AHMED OLATUNDE, OMAR BAHATTAB, ABDUR RAUF,
1.1 Introduction 3 NAVEED MUHAMMAD, YAHYA S. AL-AWTHAN,
1.2 Carbohydrates 4 TABUSSAM TUFAIL, MUHAMMAD IMRAN AND
MOHAMMAD S. MUBARAK
1.2.1 Monosaccharides 5
1.2.2 Oligosaccharides 5
3.1 Introduction 53
1.2.3 Polysaccharides 5
3.2 Biological macromolecules in biomedicine and
1.3 Lipids 9
therapies 53
1.3.1 Simple lipids 10
3.3 Carbohydrates 54
1.3.2 Compound or conjugate lipids 10
3.3.1 Therapeutics based on carbohydrates 55
1.3.3 Derived lipids 10
3.4 Peptides 56
1.4 Proteins 11
3.4.1 Therapeutics based on peptides 57
1.4.1 Simple proteins 12
3.5 Proteins 58
1.4.2 Conjugated proteins 13
3.5.1 Therapeutics based on proteins (proteins
1.4.3 Derived proteins 13
and monoclonal antibodies) 58
1.5 Nucleic acids 14
3.6 Lipids 60
1.5.1 Nucleotides 15
3.6.1 Drug delivery-based on lipids 60
1.5.2 Nucleosides 15
3.7 Nucleic acids and oligonucleotides 61
1.5.3 DNA 15
3.7.1 Therapeutics based on oligonucleotides 61
1.5.4 RNA 16
3.8 Synthesis of macromolecules 63
1.6 Conclusion 18
3.9 Biomedicine 64
References 18
3.10 Conclusions 65
References 65
2. Structure activity relationship of
biological macromolecules
4. Modification techniques for
AURELIE SARAH MOK TSZE CHUNG, YONG KIAT TEO,
WAI TENG CHENG AND JOASH BAN LEE TAN carbohydrate macromolecules
AJAY VASUDEO RANE, DEEPTI YADAV
2.1 Introduction 23 AND KRISHNAN KANNY
2.2 Enzymes as bioactive proteins 24
2.2.1 L-amino acid oxidases 25 4.1 Introduction 69

v
vi Contents

4.2 Cellulose 69 5.8.1 Polyunsaturated fatty acids 120

4.3 Hemicelluloses 71 5.8.2 The role of Omega-3 PUFAs in some
4.4 Lignin 72 disorders 121
4.5 Chitin and chitosan 72 5.9 The potential use of bioactive lipids in cancer stem
4.6 Modification of carbohydrate biological cells and coronavirus disease (COVID-19) 123
macromolecules 73 5.9.1 Bioactive lipids in cancer 123
References 86 5.9.2 Bioactive lipids in COVID-19 123
5.10 Carbohydrates as nutraceuticals 124
5.10.1 Brief overview of carbohydrates 124
II 5.10.2 Role of polysaccharides in extracellular
membrane 124
Bioactivity 5.10.3 Immunostimmulatory effect of
carbohydrates 125
5. Biological macromolecules as 5.10.4 Carbohydrates from plants with
nutraceutical activity 125
nutraceuticals
5.10.5 Cellulose and hemicellulose 125
IRERI ALEJANDRA CARBAJAL-VALENZUELA, 5.10.6 Animal derived carbohydrates with
NUVIA MARINA APOLONIO HERNANDEZ,
DIANA VANESA GUTIERREZ-CHAVEZ,
nutraceutical activity 126
BEATRIZ GONZÁLEZ-ARIAS, 5.10.7 Heparin 126
ALEJANDRA JIMENEZ-HERNANDEZ, 5.10.8 Hyaluronic acid 127
IRINEO TORRES-PACHECO, ENRIQUE RICO-GARCÍA, 5.10.9 Chitosan and chitin 127
ANA ANGELICA FEREGRINO-PÉREZ
5.10.10 Carbohydrates with nutraceutical activity
AND RAMÓN GERARDO GUEVARA-GONZÁLEZ
from microorganisms 128
5.1 History of the applications of nutraceutical 5.10.11 Alginate 128
compounds in health care 97 5.10.12 Dextran 128
5.2 Alkaloids 99 5.10.13 Bacillus striatum polysaccharide 128
5.2.1 Caffeine 99 5.11 Credit 129
5.2.2 Capsaicin 101 References 129
5.2.3 Theobromine 101
5.3 Phenolic compounds 102 6. Biological macromolecules as
5.3.1 Curcumin 102 antioxidants
5.3.2 Resveratrol 103 T. MADHUJITH, N.E. WEDAMULLA AND D.A.S. GAMAGE
5.3.3 Quercetin 103
5.3.4 Anthocyanins 103 6.1 Introduction 139
5.3.5 Luteolin 104 6.2 Types and sources of biological
5.3.6 Naringenin 104 macromolecules 141
5.3.7 Catechins 104 6.2.1 Polysaccharides 141
5.4 Terpenes 105 6.2.2 Proteins 149
5.4.1 Lycopene 105 6.2.3 Other antioxidative macromolecules 152
5.4.2 β-Carotene 105 6.3 Macromolecules as antioxidants 152
5.4.3 Lutein 106 6.3.1 Polysaccharides as antioxidants 152
5.4.4 Zeaxanthin 107 6.3.2 Proteins as antioxidants 155
5.5 Future views 107 6.3.3 Nonextractable polyphenols as
5.6 Proteins and peptides with biological activity of antioxidants 156
medical interest 107 6.4 Applications 156
5.7 Nucleic acids and their nutraceutical properties 6.4.1 Food-based applications 156
used in biomedicine 112 6.4.2 Other applications 158
5.7.1 Nucleic acids overview 112 6.5 Limitations of biological macromolecules 158
5.7.2 Perspectives 119 6.6 Future trends 159
5.8 Introduction of lipids 119 References 159
 Contents vii
7. Biological macromolecules as 8.2.1 Terpenoids 203
antimicrobial agents 8.2.2 Steroids 206
8.2.3 Phenolics 207
MD. SHAHRUZZAMAN, SHAFIUL HOSSAIN,
TANVIR AHMED, SUMAYA F. KABIR, 8.2.4 Alkaloids 208
MD. MINHAJUL ISLAM, ASHIQUR RAHMAN, 8.2.5 Polysaccharides 208
MD. SAZEDUL ISLAM, SABRINA SULTANA AND 8.2.6 Peptides 209
MOHAMMED MIZANUR RAHMAN 8.2.7 Polyketide 210
8.2.8 Polyunsaturated fatty acids 210
7.1 Introduction 165
8.3 Conclusion 213
7.2 Classification of biological macromolecule 167
References 213
7.2.1 Carbohydrate 167
7.2.2 Protein 169
7.2.3 Lipid 170 9. Biological macromolecules acting on
7.2.4 Nucleic acid 171
7.3 Antimicrobial activity of biological
central nervous system
macromolecules 172 DILIPKUMAR PAL AND KHUSHBOO RAJ

7.3.1 Polysaccharides 172

9.1 Introduction 219
7.3.2 Proteins 175
9.1.1 Proteins 219
7.3.3 Fatty acids 177
9.1.2 Cell cycle proteins 220
7.4 Antimicrobial activity of macromolecule
9.1.3 Homer/vesl proteins 220
composites 180
9.1.4 Central fatty hypothesis 222
7.4.1 Chitosan-alginate 180
9.1.5 Carbohydrates 222
7.4.2 Gelatin-chitosan 181
9.1.6 Role of carbohydrates on nervous
7.4.3 Keratin-chitosan 182
system 223
7.4.4 Collagen-alginate 183
9.1.7 In sensory organs 223
7.4.5 Chitosan-cellulose 184
9.1.8 Glycans 223
7.4.6 Lactoferrin-Oleic Acid 185
9.1.9 Role of glycan in neural development 224
7.5 Nanotechnology based antimicrobial
9.1.10 Lipids 224
macromolecule 185
9.1.11 Role of cPLA2 in cerebral ischemia 225
7.5.1 Chitosan based nanocomposite 185
9.1.12 In the case of neurodegenerative
7.5.2 Alginate-based nanocomposite 187
diseases 225
7.5.3 Cellulose based nanocomposite 187
9.1.13 Lipid peroxidation 225
7.5.4 Gelatin based nanocomposite 189
9.2 Conclusion 226
7.5.5 Collagen based nanocomposite 190
References 226
7.5.6 Keratin-based nanoparticle 190
7.5.7 Oleic acid based nanoparticle 190
7.6 Applications 190
7.6.1 Food packaging 190
10. Biological macromolecules as
7.6.2 Drug delivery 191 antidiabetic agents
7.6.3 Wound dressing 192 JAISON JEEVANANDAM, CALEB ACQUAH
7.7 Conclusion 193 AND MICHAEL K. DANQUAH

References 193
10.1 Introduction 229
8. Biological macromolecules from algae 10.2 Types of biological macromolecules 230
and their antimicrobial applications 10.3 Biological macromolecules 232
10.3.1 Carbohydrates 232
NATANAMURUGARAJ GOVINDAN,
GAANTY PRAGAS MANIAM, MOHD HASBI AB. RAHIM,
10.3.2 Lipids 233
AHMAD ZIAD SULAIMAN AND AZILAH AJIT 10.3.3 Proteins 235
10.3.4 Nucleic acids 237
8.1 Introduction 203 10.4 Advantages, limitations, and future
8.2 Bioactive macromolecules 203 perspectives 238
viii Contents

10.5 Conclusion 238 14. Synthetic macromolecules with

References 239
11. Biological macromolecules as
anticancer agents
HIMJA TIWARI, HARSHAL DESHMUKH,
NILESH SHIRISH WAGH AND JAYA LAKKAKULA
11.1 Introduction 243
11.2 Biological macromolecules for cancer therapy
11.2.1 Carbohydrates 244
11.2.2 Proteins and nucleic acid 258
11.2.3 Lipids 262
11.3 Conclusion 269
References 269
12. Biological macromolecules as
immunomodulators
EDUARDO COSTA, MANUELA MACHADO,
MANUELA PINTADO AND SARA SILVA
12.1 Introduction 273
12.2 Immunomodulation 274
12.3 Immunomodulation, biomolecules, and
applications 274
12.4 Polysaccharides 275
12.4.1 Immunomodulatory polysaccharides 275
12.4.2 Gut microbiota modulation 277
12.5 Lipids 277
12.5.1 Immunomodulatory effect of lipids 278
12.6 Proteins 280
12.6.1 Known immunomodulatory proteins 280
Acknowledgments 282
References 282
13. Biological macromolecules acting on
gastrointestinal systems
DILIPKUMAR PAL AND SUPRIYO SAHA
13.1 Introduction 289
13.2 Role of carbohydrates in gastrointestinal
system 289
13.3 Role of proteins in gastrointestinal system 295
13.4 Role of fatty acids in gastrointestinal system 298
13.5 Role of nucleic acids in gastrointestinal
system 300
13.6 Conclusion 301
References 302
biological activity
STEFANIA RACOVITA, MARCEL POPA,
LEONARD IONUT ATANASE AND SILVIA VASILIU
14.1 Introduction 305
14.2 Synthetic macromolecules with antimicrobial
activity 306
14.2.1 History of antimicrobial agents and
244 antimicrobial polymers 307
14.2.2 Classification of antimicrobial
polymers 308
14.2.3 Preparation routes for antimicrobial
polymers 309
14.2.4 Factors affecting the antimicrobial
activity 311
14.2.5 Synthetic macromolecules with
antibacterial activity 313
14.2.6 Synthetic macromolecules with antiviral
activity 317
14.2.7 Synthetic macromolecules with antifungal
activity 318
14.2.8 Synthetic macromolecules with
antiparasitic activity 319
14.3 Synthetic macromolecules with antioxidant
activity 320
14.4 Polymer sequestrants 324
14.5 Conclusions 328
References 328
Further reading 335
III
Functional applications
15. Biological macromolecules in drug
delivery
AMIT KUMAR NAYAK, MD SAQUIB HASNAIN,
ANINDITA BEHERA, AMAL KUMAR DHARA AND
DILIPKUMAR PAL
15.1 Introduction 339
15.2 Drug delivery using various biological
macromolecules 340
15.2.1 Drug delivery using carbohydrates 341
15.2.2 Drug delivery using proteins and
peptides 349
15.2.3 Drug delivery using nucleic acids 355
 Contents ix
15.2.4 Drug delivery using lipids 359 18.4 Biological macromolecules for delivery systems of
15.3 Conclusion 367 growth factors 424
References 367 18.4.1 Protein-based materials for growth factor
delivery 425
16. Biological macromolecules in tissue 18.4.2 Polysaccharide-based materials for growth
engineering factor delivery 427
18.4.3 Polysaccharide combinations for growth
PANDURANG APPANA DALAVI,
SESHA SUBRAMANIAN MURUGAN, factor delivery 429
SUKUMARAN ANIL AND JAYACHANDRAN VENKATESAN 18.4.4 Composites materials for growth factor
delivery 430
16.1 Introduction 381 18.4.5 Protein-based composite for growth factor
16.2 Bone tissue engineering 381 delivery 430
16.3 Biological macromolecules in bone tissue 18.4.6 Protein-polysaccharide composites for
engineering 382 growth factor delivery 432
16.3.1 Alginate 382 18.4.7 Polysaccharide-polysaccharide composites
16.3.2 Chitosan 383 for growth factor delivery 433
16.3.3 Carrageenan 384 References 433
16.3.4 Fucoidan 385
16.3.5 Ulvan 385 19. Biological macromolecules for growth
16.3.6 Gelatin 386 factor delivery in bone regeneration
16.4 Conclusion 387
ARISTEIDIS PAPAGIANNOPOULOS AND ELENI VLASSI
Acknowledgment 387
References 387 19.1 Introduction 439
19.2 Bone regeneration 439
17. Biological macromolecules for drug 19.3 Growth factors in tissue and bone
delivery in tissue engineering regeneration 441
MARCEL POPA AND LEONARD IONUT ATANASE 19.4 Biomacromolecules as carriers of growth
factors 443
17.1 Introduction 393 19.5 Hydrogels and sponges 445
17.2 Drug-loaded electrospun fibers used in tissue 19.6 Scaffolds and fibers 446
engineering applications and drug delivery 394 19.7 Nanoparticles and nanoassemblies 448
17.2.1 Drug-loaded polysaccharides-based 19.8 Concluding remarks 449
electrospun fibers 395 References 449
17.2.2 Drug-loaded protein-based electrospun
fibers 401 20. Biological macromolecules for
17.3 Drug-loaded injectable hydrogels used in tissue nutrients delivery
engineering applications and drug delivery 403
LONG CHEN, ZHONGYU YANG, DAVID JULIAN
17.4 Conclusions 411 MCCLEMENTS, ZHENGYU JIN AND MING MIAO
References 411
20.1 Introduction 455
18. Biological macromolecules for growth 20.2 Nutrients 455
factor delivery 20.2.1 Water-soluble nutrients 456
M.D. FIGUEROA-PIZANO 20.2.2 Oil-soluble nutrients 458
20.3 Biological macromolecules used for nutrients
18.1 Introduction 419 delivery 458
18.2 Delivery systems for growth factors 421 20.3.1 Polysaccharides 459
18.3 Materials for delivery systems of growth 20.3.2 Proteins 461
factors 423 20.3.3 Glycoproteins and proteoglycans 461
x Contents

20.3.4 Others (lignin as example) 462 22.2.4 Collagen 500

20.4 Molecular interactions that maintain the stability 22.2.5 Gelatin 503
of biopolymer-based delivery systems 462 22.2.6 Fibrin 504
20.4.1 Electrostatic interactions 463 22.2.7 Glycosaminoglycans 505
20.4.2 Hydrogen bonding 463 22.2.8 Silk (fibroion and spidroin) 506
20.4.3 Hydrophobic interactions 463 22.2.9 Other natural polymers in TE 508
20.4.4 Covalent interactions 464 22.3 Advantages, drawbacks, applications, forms and
20.5 Retention and release mechanisms 464 manufacturing methods 511
20.6 Nutrient delivery systems based on biological 22.4 Conclusions 526
macromolecules 465 Acknowledgment 527
20.6.1 Composition and structure 465 References 527
20.6.2 Fabrication 466
20.6.3 Properties 469 23. Biological macromolecules for enzyme
20.6.4 Applications 469 immobilization
20.7 Future trends 471
HAMZA RAFEEQ, SARMAD AHMAD QAMAR,
20.7.1 Co-encapsulation of multiple HIRA MUNIR, MUHAMMAD BILAL AND HAFIZ M.N. IQBAL
nutrients 471
20.7.2 Targeted and controlled release of 23.1 Introduction 529
bioactive molecules 471 23.2 Biological macromolecules for enzyme
20.7.3 In vivo testing 472 immobilization 532
References 472 23.2.1 Chitin and chitosan 532
23.2.2 Agarose 533
21. Biological macromolecules for nucleic 23.2.3 Alginate 534
acid delivery 23.2.4 Cellulose and its derivatives 535
AHMED S. ABO DENA AND IBRAHIM M. EL-SHERBINY
23.2.5 Gelatin for enzyme immobilization 536
23.2.6 Dextran for enzyme immobilization 537
21.1 Introduction 479 23.2.7 Pectin for enzyme immobilization 539
21.2 Nucleic acids structure and functions 480 23.2.8 Xanthan for enzyme immobilization 540
21.3 Biological macromolecules for nucleic acid 23.3 Conclusions and future outlook 541
delivery 482 Acknowledgment 541
21.3.1 Lipid-based drug delivery systems 482 Conflicts of interest 541
21.3.2 Protein-based drug delivery systems 484 References 542
21.3.3 Carbohydrate-based drug delivery Further reading 546
systems 486
21.4 Conclusions 488 24. Carbohydrates mimetics: enzyme
References 489 inhibitors and target molecules in several
diseases
22. Biological macromolecules in cell VERÓNICA E. MANZANO, CUSTODIANA A.
encapsulation COLMENAREZ LOBO AND EVANGELINA REPETTO
MILAN MILIVOJEVIC, IVANA PAJIC-LIJAKOVIC AND
BRANKO BUGARSKI 24.1 Introduction 547
24.1.1 Biomass and biobased materials 547
22.1 Introduction 491 24.1.2 Carbohydrates 548
22.2 Biopolymers used for cell encapsulation in 24.1.3 Biological and medicinal interest of
TE 496 carbohydrates 550
22.2.1 Agarose 496 24.1.4 Glycosidases 551
22.2.2 Alginate 497 24.2 Glycomimetics 554
22.2.3 Chitin and chitosan 499 24.2.1 Iminosugars 554
 Contents xi
24.2.2 Carbasugars 561 25.5.2 Gene delivery 592
24.2.3 Thiosugars 564 25.6 Macromolecules on tissue engineering 593
24.3 Hybrid carbohydrates 566 25.6.1 Wound management 597
24.4 Macromolecules 567 25.6.2 Development of skin substitutes 597
24.4.1 Multivalents 567 25.7 Conclusion 600
24.4.2 Polysaccharides 569 References 600
24.5 Conclusions 570
References 570 26. Future perspectives of biological
macromolecules in biomedicine
IV ANA R. NEVES, RÚBEN FARIA, TÂNIA ALBUQUERQUE,
TELMA QUINTELA, ÂNGELA SOUSA AND DIANA COSTA

Others 26.1 Bio-nanotechnology 607

25. Current challenging issues of
biological macromolecules in biomedicine
Y. DE ANDA-FLORES, E. CARVAJAL-MILLAN,
A.C. CAMPA-MADA, K.G. MARTÍNEZ-ROBINSON,
J. LIZARDI-MENDOZA, A. RASCÓN-CHU,
A.L. MARTÍNEZ-LÓPEZ AND J. TANORI-CORDOVA
25.1 Introduction 581
25.2 Biological macromolecules 582
25.3 Macromolecules in biomedical applications 583
25.4 Macromolecules in targeted drug delivery 584
25.5 Biomaterials as targeted drug delivery 585
25.5.1 Hydrogels for drug delivery 585
26.1.1 Delivery systems 608
26.2 Mitochondrial gene therapy 610
26.2.1 Mitochondrion 611
26.2.2 Mitochondrial mutations 611
26.2.3 Targeting Mitochondria 612
26.3 Crosstalk between chronobiology and cancer 616
26.3.1 Circadian clock and cancer
development 617
26.3.2 Chronobiology and cancer treatment 619
26.4 Concluding remarks 624
References 625
Index 633
 List of contributors
Ahmed S. Abo Dena Nanomedicine Laboratory,
Center for Materials Science, Zewail City of
Science and Technology, Giza, Egypt;
Department of Pharmaceutical Chemistry,
National Organization for Drug Control and
Research (NODCAR), Giza, Egypt
Caleb Acquah School of Nutrition Sciences,
Faculty of Health Sciences, University of Ottawa,
Ottawa, ON, Canada
Tanvir Ahmed Department of Applied Chemistry
and Chemical Engineering, Faculty of
Engineering and Technology, University of
Dhaka, Dhaka, Bangladesh
Azilah Ajit Faculty of Chemical & Natural
Resources Engineering, Universiti Malaysia
Pahang, Kuantan, Malaysia
Yahya S. Al-Awthan Department of Biology,
Faculty of Science, University of Tabuk, Tabuk,
Saudia Arabia; Department of Biology, Faculty of
Science, Ibb University, Ibb, Yemen
Tânia Albuquerque CICS-UBI—Health Sciences
Research Centre, University of Beira Interior,
Covilhã, Portugal
Sukumaran Anil Department of Dentistry, Oral
Health Institute, Hamad Medical Corporation,
College of Dental Medicine, Qatar University,
Doha, Qatar
Nuvia Marina Apolonio–Hernandez Biosystems
Engineering Group, School of Engineering-
Campus Amazcala, Autonomous University of
Querétaro (México), Querétaro, México
Leonard Ionut Atanase Academy of Romanian
Scientists, Bucuresti, Romania; Faculty of Dental
Medicine, “Apollonia” University of Iasi, Iasi,
Romania
Omar Bahattab Department of Biology, Faculty of
Science, University of Tabuk, Tabuk, Saudia Arabia
xiii
Anindita Behera School of Pharmaceutical
Sciences, Siksha “O” Anusandhan, Deemed to be
University, Bhubaneswar, India
Muhammad Bilal School of Life Science and Food
Engineering, Huaiyin Institute of Technology,
Huai’an, China
Branko Bugarski Department of Chemical
Engineering, Faculty of Technology and Metallurgy,
University of Belgrade, Belgrade, Serbia
A.C. Campa-Mada Biopolymers-CTAOA,
Research Center for Food and Development
(CIAD, A.C.), Hermosillo, Mexico
Ireri Alejandra Carbajal-Valenzuela Biosystems
Engineering Group, School of Engineering-
Campus Amazcala, Autonomous University of
Querétaro (México), Querétaro, México
E. Carvajal-Millan Biopolymers-CTAOA, Research
Center for Food and Development (CIAD, A.C.),
Hermosillo, Mexico
Long Chen School of Food Science and
Technology, Jiangnan University, Wuxi, P.R.
China; State Key Laboratory of Food Science and
Technology, Jiangnan University, Wuxi, P.R. China
Wai Teng Cheng School of Science, Monash
University Malaysia, Bandar Sunway, Malaysia
Custodiana A. Colmenarez Lobo Research Center
in Carbohydrate Chemistry (CIHIDECAR),
National Scientific and Technical Research
Council (CONICET)-UBA, Buenos Aires,
Argentina
Diana Costa CICS-UBI—Health Sciences Research
Centre, University of Beira Interior, Covilhã,
Portugal
Eduardo Costa Universidade Católica Portuguesa,
CBQF—Centro de Biotecnologia e Quı́mica Fina
—Laboratório Associado, Escola Superior de
Biotecnologia, Porto, Portugal
xiv List of contributors
Pandurang Appana Dalavi Biomaterials Research
Laboratory, Yenepoya Research Centre,
Yenepoya (Deemed to be University),
Deralakatte, Mangalore, India
Michael K. Danquah Chemical Engineering
Department, University of Tennessee,
Chattanooga, TN, United States
Y. De Anda-Flores Biopolymers-CTAOA, Research
Center for Food and Development (CIAD, A.C.),
Hermosillo, Mexico
Harshal Deshmukh Amity Institute of
Biotechnology, Amity University Maharashtra,
Mumbai, —Pune Expressway, Bhatan Post—
Somathne, Panvel, Mumbai, India
Amal Kumar Dhara Department of Pharmacy,
Contai Polytechnic, Contai, India
Ibrahim M. El-Sherbiny Nanomedicine
Laboratory, Center for Materials Science, Zewail
City of Science and Technology, Giza, Egypt
Rúben Faria CICS-UBI—Health Sciences Research
Centre, University of Beira Interior, Covilhã,
Portugal
Ana Angelica Feregrino-Pérez Biosystems
Engineering Group, School of Engineering-
Campus Amazcala, Autonomous University of
Querétaro (México), Querétaro, México
M.D. Figueroa-Pizano Biopolymers-CTAOA,
Research Center for Food and Development
(CIAD), Hermosillo, Sonora, Mexico
D.A.S. Gamage Department of Chemical and
Process Engineering, Faculty of Engineering,
University of Peradeniya, Peradeniya, Sri
Lanka
Beatriz González-Arias Biosystems Engineering
Group, School of Engineering-Campus Amazcala,
Autonomous University of Querétaro (México),
Querétaro, México
Natanamurugaraj Govindan Algae Culture
Collection Center & Laboratory, Faculty of
Industrial Sciences and Technology, Universiti
Malaysia Pahang, Kuantan, Malaysia; Centre for
Research in Advanced Tropical Bioscience,
Universiti Malaysia Pahang, Kuantan, Malaysia
Ramón Gerardo Guevara-González Biosystems
Engineering Group, School of Engineering-
Campus Amazcala, Autonomous University of
Querétaro (México), Querétaro, México
Diana Vanesa Gutierrez-Chavez Biosystems
Engineering Group, School of Engineering-
Campus Amazcala, Autonomous University of
Querétaro (México), Querétaro, México
Md Saquib Hasnain Department of Pharmacy,
Palamau Institute of Pharmacy, Daltonganj, India
Shafiul Hossain Department of Applied
Chemistry and Chemical Engineering, Faculty of
Engineering and Technology, University of
Dhaka, Dhaka, Bangladesh; Department of
Chemical Engineering and Polymer Science,
Shahjalal University of Science and Technology,
Sylhet, Bangladesh
Muhammad Imran University Institute of Diet &
Nutritional Sciences, Faculty of Allied Health
Sciences, The University of Lahore, Lahore,
Pakistan
Hafiz M.N. Iqbal Tecnologico de Monterrey,
School of Engineering and Sciences, Monterrey,
Mexico
Jaison Jeevanandam CQM—Centro de Quı́mica
da Madeira (Madeira Chemistry Center), MMRG,
Universidade da Madeira (University of
Madeira), Campus da Penteada (Penteada cam-
pus), Funchal, Portugal
Alejandra Jimenez-Hernandez Biosystems
Engineering Group, School of Engineering-
Campus Amazcala, Autonomous University of
Querétaro (México), Querétaro, México
Zhengyu Jin School of Food Science and
Technology, Jiangnan University, Wuxi, P.R.
China; State Key Laboratory of Food Science and
Technology, Jiangnan University, Wuxi, P.R.
China
Sumaya F. Kabir Department of Applied
Chemistry and Chemical Engineering, Faculty of
Engineering and Technology, University of
Dhaka, Dhaka, Bangladesh
Krishnan Kanny Composite Research Group,
Department of Mechanical Engineering, Durban
University of Technology, Durban, South Africa
Jaya Lakkakula Amity Institute of Biotechnology,
Amity University Maharashtra, Mumbai, —Pune
Expressway, Bhatan Post—Somathne, Panvel,
Mumbai, India
J. Lizardi-Mendoza Biopolymers-CTAOA,
Research Center for Food and Development
(CIAD, A.C.), Hermosillo, Mexico
 List of contributors xv
Manuela Machado Universidade Católica Mohammad S. Mubarak Department of
Portuguesa, CBQF—Centro de Biotecnologia e Chemistry, The University of Jordan, Amman,
Quı́mica Fina—Laboratório Associado, Escola Jordan
Superior de Biotecnologia, Porto, Portugal Naveed Muhammad Department of Pharmacy,
T. Madhujith Department of Food Science and Abdul Wali Khan University, Khyber
Technology, Faculty of Agriculture, University of Pakhtunkhwa, Pakistan
Peradeniya, Peradeniya, Sri Lanka Hira Munir Department of Biochemistry and
Gaanty Pragas Maniam Algae Culture Collection Biotechnology, University of Gujrat, Gujrat,
Center & Laboratory, Faculty of Industrial Pakistan
Sciences and Technology, Universiti Malaysia Sesha Subramanian Murugan Biomaterials
Pahang, Kuantan, Malaysia; Centre for Research Research Laboratory, Yenepoya Research Centre,
in Advanced Tropical Bioscience, Universiti Yenepoya (Deemed to be University),
Malaysia Pahang, Kuantan, Malaysia Deralakatte, Mangalore, India
Verónica E. Manzano Faculty of Exact and Amit Kumar Nayak Department of
Natural Sciences, Department of Organic Pharmaceutics, Seemanta Institute of
Chemistry, University of Buenos Aires, Buenos Pharmaceutical Sciences, Jharpokharia, India
Aires, Argentina; Research Center in
Carbohydrate Chemistry (CIHIDECAR), National Ana R. Neves CICS-UBI—Health Sciences
Scientific and Technical Research Council Research Centre, University of Beira Interior,
(CONICET)-UBA, Buenos Aires, Argentina Covilhã, Portugal
Ahmed Olatunde Department of Biochemistry,
A.L. Martı́nez-López NANO-VAC Research
Abubakar Tafawa Balewa University, Bauchi,
Group, Department of Chemistry and
Nigeria
Pharmaceutical Technology, University of
Navarra, Pamplona, Spain Ivana Pajic-Lijakovic Department of Chemical
Engineering, Faculty of Technology and
K.G. Martı́nez-Robinson Biopolymers-CTAOA,
Metallurgy, University of Belgrade, Belgrade,
Research Center for Food and Development
Serbia
(CIAD, A.C.), Hermosillo, Mexico
Dilipkumar Pal Department of Pharmaceutical
David Julian McClements Department of Food Sciences, Guru Ghasidas Vishwavidyalaya (A
Science, University of Massachusetts, Amherst, Central University), Bilaspur, India
MA, United States
Aristeidis Papagiannopoulos Theoretical and
Ming Miao School of Food Science and Physical Chemistry Institute, National Hellenic
Technology, Jiangnan University, Wuxi, P.R. Research Foundation, Athens, Greece
China; State Key Laboratory of Food Science and
Manuela Pintado Universidade Católica
Technology, Jiangnan University, Wuxi, P.R.
Portuguesa, CBQF—Centro de Biotecnologia e
China
Quı́mica Fina—Laboratório Associado, Escola
Milan Milivojevic Department of Chemical Superior de Biotecnologia, Porto, Portugal
Engineering, Faculty of Technology and
Marcel Popa “Apollonia” University of Iasi,
Metallurgy, University of Belgrade, Belgrade,
Faculty of Dental Medicine, Iasi, Romania;
Serbia
Academy of Romanian Scientists, Bucuresti,
Md. Minhajul Islam Department of Applied Romania; Faculty of Chemical Engineering and
Chemistry and Chemical Engineering, Faculty of Environmental Protection, Department of Natural
Engineering and Technology, University of and Synthetic Polymers, “Gheorghe Asachi”
Dhaka, Dhaka, Bangladesh Technical University of Iasi, Iasi, Romania
Aurelie Sarah Mok Tsze Chung School of Science, Sarmad Ahmad Qamar Department of
Monash University Malaysia, Bandar Sunway, Biochemistry, University of Agriculture,
Malaysia Faisalabad, Pakistan
xvi List of contributors
Telma Quintela CICS-UBI—Health Sciences
Research Centre, University of Beira Interior,
Covilhã, Portugal
Stefania Racovita “Petru Poni” Institute of
Macromolecular Chemistry, Iasi, Romania
Hamza Rafeeq Department of Biochemistry,
University of Agriculture, Faisalabad, Pakistan
Mohd Hasbi Ab. Rahim Algae Culture Collection
Center & Laboratory, Faculty of Industrial
Sciences and Technology, Universiti Malaysia
Pahang, Kuantan, Malaysia; Centre for Research
in Advanced Tropical Bioscience, Universiti
Malaysia Pahang, Kuantan, Malaysia
Ashiqur Rahman Department of Applied
Chemistry and Chemical Engineering, Faculty of
Engineering and Technology, University of
Dhaka, Dhaka, Bangladesh; National Institute of
Textile Engineering and Research (NITER),
Dhaka, Bangladesh
Mohammed Mizanur Rahman Department of
Applied Chemistry and Chemical Engineering,
Faculty of Engineering and Technology,
University of Dhaka, Dhaka, Bangladesh
Khushboo Raj School of Pharmacy, Arka Jain uni-
versity, Tata, Jamshedpur, India
Ajay Vasudeo Rane Composite Research Group,
Department of Mechanical Engineering, Durban
University of Technology, Durban, South Africa
A. Rascón-Chu Biotechnology-CTAOV, Research
Center for Food and Development (CIAD, A.C.),
Hermosillo, Mexico
Abdur Rauf Department of Chemistry, University
of Swabi Anbar, Khyber Pakhtunkhwa, Pakistan
Evangelina Repetto Faculty of Exact and Natural
Sciences, Department of Organic Chemistry,
University of Buenos Aires, Buenos Aires,
Argentina; Research Center in Carbohydrate
Chemistry (CIHIDECAR), National Scientific and
Technical Research Council (CONICET)-UBA,
Buenos Aires, Argentina
Enrique Rico-Garcı́a Biosystems Engineering
Group, School of Engineering-Campus Amazcala,
Autonomous University of Querétaro (México),
Querétaro, México
Supriyo Saha School of Pharmaceutical Sciences
and Technology, Sardar Bhagwan Singh
University, Dehradun, India
Md. Sazedul Islam Department of Applied
Chemistry and Chemical Engineering, Faculty of
Engineering and Technology, University of
Dhaka, Dhaka, Bangladesh
Md. Shahruzzaman Department of Applied
Chemistry and Chemical Engineering, Faculty of
Engineering and Technology, University of
Dhaka, Dhaka, Bangladesh
Sara Silva Universidade Católica Portuguesa,
CBQF—Centro de Biotecnologia e Quı́mica Fina
—Laboratório Associado, Escola Superior de
Biotecnologia, Porto, Portugal
Ângela Sousa CICS-UBI—Health Sciences
Research Centre, University of Beira Interior,
Covilhã, Portugal
Ahmad Ziad Sulaiman Faculty of Bio-Engineering
& Technology, University Malaysia Kelantan
Kampus Jeli, Kelantan, Malaysia
Sabrina Sultana Department of Applied
Chemistry and Chemical Engineering, Faculty of
Engineering and Technology, University of
Dhaka, Dhaka, Bangladesh; Department of Arts
and Sciences, Ahsanullah University of Science
and Technology, Dhaka, Bangladesh
Joash Ban Lee Tan School of Science, Monash
University Malaysia, Bandar Sunway, Malaysia
J. Tanori-Cordova Department of Polymers and
Materials Research, University of Sonora,
Hermosillo, Mexico
Yong Kiat Teo School of Science, Monash
University Malaysia, Bandar Sunway, Malaysia
Himja Tiwari Amity Institute of Biotechnology,
Amity University Maharashtra, Mumbai, —Pune
Expressway, Bhatan Post—Somathne, Panvel,
Mumbai, India
Irineo torres-Pacheco Biosystems Engineering
Group, School of Engineering-Campus Amazcala,
Autonomous University of Querétaro (México),
Querétaro, México
Tabussam Tufail University Institute of Diet &
Nutritional Sciences, Faculty of Allied Health
Sciences, The University of Lahore, Lahore,
Pakistan
 List of contributors xvii
Silvia Vasiliu “Petru Poni” Institute of N.E. Wedamulla Department of Export
Macromolecular Chemistry, Iasi, Romania Agriculture, Faculty of Animal Science and
Jayachandran Venkatesan Biomaterials Research Export Agriculture, Uva Wellassa University,
Laboratory, Yenepoya Research Centre, Badulla, Sri Lanka
Yenepoya (Deemed to be University), Deepti Yadav Department of Biotechnology and
Deralakatte, Mangalore, India Food Science, Durban University of Technology,
Eleni Vlassi Theoretical and Physical Chemistry Durban, South Africa
Institute, National Hellenic Research Foundation, Zhongyu Yang School of Food Science and
Athens, Greece Technology, Jiangnan University, Wuxi, P.R.
Nilesh Shirish Wagh Amity Institute of China
Biotechnology, Amity University Maharashtra,
Mumbai, —Pune Expressway, Bhatan Post—
Somathne, Panvel, Mumbai, India
 Preface
The scope of this book, entitled Biological
Macromolecules: Bioactivity and Biomedical
Applications, is the coverage and review of
recent trends and applications of biological
macromolecules, such as carbohydrates, lipids,
proteins, peptides, and nucleic acids in biome-
dicines, drug delivery, growth factors delivery,
nutrients and nucleic acids delivery, cell encap-
sulation, enzyme mobilization, and tissue
engineering.
The mysteries of life lie in biological macro-
molecules. A large volume of biological macro-
molecules is obtained from different biological
origins such as plants, algae, fungi, animals,
and microbial sources. Biological macromole-
cules exhibit some significant and favorable
advantages over synthetic macromolecules,
such as sustainable and economic production,
biocompatibility, biodegradability, and
improved bioavailability. In recent years, a
plethora of biological macromolecules (carbo-
hydrates, lipids, proteins, peptides, and nucleic
acids) has been used in the biomedical and
healthcare fields. They showed varieties of
bioactivities such as antioxidant, anticancer,
antidiabetic, antimicrobial, immunomodula-
tory activities on the central nervous system,
and gastrointestinal activity. The other biomed-
ical applications include drug delivery, growth
factors delivery, nutrients and nucleic acids
delivery, cell encapsulation, enzyme mobiliza-
tion, and tissue engineering. The structure-
property relationship is also an important
aspect for a thorough understanding of the bio-
activity of biological macromolecules.
xix
This book, containing 4 sections and 26
chapters, provides a systematic insight into the
inclusive discussions on bioactivity and bio-
medical applications of different biological
macromolecules. We are glad to see that many
authors across the globe accepted our invita-
tion and contributed valued chapters for this
book, covering a wide spectrum of fields. A
concise account of the contents of each chapter
has been described to provide a glimpse of the
book to the potential readers of various fields.
The topics in the book (in order of prefer-
ence) include the following: Biological
Macromolecules: Sources, Properties, and functions
(Chapter 1)—this chapter describes sources
physicochemical properties, bioactivity and
biomedical applications of different biological
macromolecules concisely; Structure Activity
Relationship of Biological Macromolecules
(Chapter 2)—this chapter aims to provide an
overview of the structural features influencing
the bioactivities of biological macromolecules,
namely L-amino acid oxidases, lysostaphin,
and metallo-β-lactamase-such as lactonase and
chitosan; The Importance of Biological
Macromolecules in Biomedicine (Chapter 3)—this
chapter highlights the therapeutic aspects of
macromolecules and the medicinal use of bio-
logical macromolecules against various dis-
eases and ailments; Modification Techniques for
Carbohydrate Macromolecules (Chapter 4)—this
chapter characteristically abridges the signifi-
cant developments of the last five to ten years
and discusses critically in the area of modifica-
tion of carbohydrates macromolecules;
xx Preface
Biological Macromolecules as Nutraceuticals
(Chapter 5)—this chapter aims to demonstrate
some recent knowledge regarding the nutra-
ceutical and biological activities of the macro-
molecules of biological origin, as well as some
frontier applications of these in healthcare;
Biological Macromolecules as Antioxidants
(Chapter 6)—this chapter highlights the poten-
tial applications of biological macromolecules
as antioxidants to scavenge reactive oxygen
species and control oxidative stress, which
leads to various pathogenesis; Biological
Macromolecules as Antimicrobial Agents
(Chapter 7)—the chapter describes the antimi-
crobial activity of biological macromolecules
(chitosan, cellulose, alginate, gelatin, collagen,
and keratin) and also, comprehensively eluci-
dates their applications in addressing chal-
lenges associated with drug delivery, wound
dressing, food packaging, and so on Biological
Macromolecules From Algae and Their
Antimicrobial Applications (Chapter 8) this
chapter provides an overview of bioactive
macromolecules and their antimicrobial activi-
ties with particular reference to algal sources;
Biological Macromolecules Acting on Central
Nervous System (Chapter 9)—in this chapter,
the role of biological macromolecules on cen-
tral nervous system and their critical role in
downregulation after the various neurological
disorders have been discussed; Biological
Macromolecules as Antidiabetic Agents
(Chapter 10)—this chapter is an overview of
different types of biological macromolecules
and their applications as potential antidiabetic
agents and also, highlights the advantages, lim-
itations and future perspectives of biological
macromolecules as antidiabetic agents;
Biological Macromolecules as Anticancer Agents
(Chapter 11)—this chapter presents the extrac-
tion of macromolecules such as carbohydrate,
proteins, lipids, and nucleic acid (miRNAs)
from different biological sources, such as
plants, animal, algae and fungi. The various
mechanisms by which the macromolecules
exhibit their anticancer activity have been
discussed briefly along with several assays
done to evaluate cytotoxicity of the macromole-
cules against various cancers such as lung can-
cer, breast cancer, cervical cancer, and colon
cancer. Biological Macromolecules as
Immunomodulators (Chapter 12)—this topic
focuses on the potential modulations of
immune response of biomacromolecules (three
major classes of compounds: lipids, proteins
and polysaccharides); Biological Macromolecules
Acting on Gastrointestinal Systems
(Chapter 13)—this chapter describes the role of
biological macromolecules for the management
of gastrointestinal system and related disor-
ders; Synthetic Macromolecules With Biological
Activity (Chapter 14)—this chapter describes
some classes of synthetic macromolecules with
biological activity that have a great importance
on the human comfort and health, including
antimicrobial polymers, antioxidant polymers,
and polymeric sequestrants; Biological
Macromolecules in Drug Delivery (Chapter 15)—
this chapter focuses on the advancements in
the uses of various biological macromolecules
in drug delivery applications; Biological macro-
molecules in tissue engineering (Chapter 16)—this
chapter provides an overview on the important
role of natural-derived biomaterials (alginate,
chitosan, carrageenan, fucoidan, ulvan, colla-
gen, and gelatin) combining with ceramic bio-
materials for bone tissue construction;
Biological Macromolecules for Drug Delivery in
Tissue Engineering (Chapter 17)—This chapter
is focused on the preparation and physico-
chemical characterization of engineered bioma-
terials, based on biological macromolecules
(polysaccharides and proteins), as scaffolds
which are capable of supporting physiological
activities of cells, but also can act as drug deliv-
ery systems for tissue engineering and wound
healing; Biological Macromolecules for Growth
Factor Delivery (Chapter 18)—this chapter dis-
cusses the fabrication of synthetic and natural
macromolecules, sometimes combined with
other mineral or metallic compounds for
growth factor delivery; Biological
 Preface
Macromolecules for Growth Factor Delivery in
Bone Regeneration (Chapter 19)—this chapter
describes the process of bone tissue regenera-
tion in healing injuries and arthritic conditions,
introduces the main ideas through the scope of
allogenous and autogenous transplantation
and demonstrates the role of growth factors in
these processes; Biological Macromolecules for
Nutrients Delivery (Chapter 20)—This chapter
focuses on the types of nutrients that need to
be delivered, the biological macromolecules
that can be used to construct edible delivery
systems, the most common delivery systems
currently used for this purpose, and some of
the major challenges that must be addressed in
the future; Biological Macromolecules for Nucleic
Acid Delivery (Chapter 21)—this chapter
describes the nonviral nucleic acid delivery
systems made up of biological macromole-
cules, such as peptides, lipids, and carbohy-
drates and also gives an introduction on the
history and structure of nucleic acids; Biological
Macromolecules in Cell Encapsulation
(Chapter 22)—this chapter aims to review the
most examined, most promising and recently
proposed biopolymers that are used in tissue
engineering scaffolds, and to highlight their
main properties, drawbacks, fields of applica-
tions and fabrication technologies in order to
provide readers with important guidelines for
selecting appropriate scaffold biomaterials;
Biological Macromolecules for Enzyme
Immobilization (Chapter 23)—this chapter pro-
vides a broad overview of properties and the
applications of various naturally occurring bio-
polymers, that is, chitosan, chitin, agarose, algi-
nates, cellulose, gelatin, dextran, carrageenan,
pectin and xanthan gum for their applications
in enzyme immobilization with recent litera-
ture studies indicating biopolymer-based sup-
port material development and their utilization
to make biocatalysts with desired stability and
catalytic functionalities; Carbohydrates for
Enzyme Inhibition and Their Use as Target
Molecules for the Interference of Diseases
(Chapter 24)—this chapter describes the study
of a widespread group of enzymes and the
xxi
inhibition of these enzymes constitutes an
interesting and novel strategy to approach new
therapies against numerous diseases; Current
Challenging Issues of Biological Macromolecules in
Biomedicine (Chapter 25)—this chapter provides
information on recent innovations in various
biomaterials, engineered from macromolecules
ranging from drug delivery, cancer therapies,
tissue engineering, bioprinting and wound
healing; Future Perspectives of Biological
Macromolecules in Biomedicine (Chapter 26)—
this chapter discusses the impact of the combi-
nation of nanotechnology and chronobiology
in personalized cancer treatment.
We sincerely acknowledge the valuable con-
tribution of the distinguished authors and con-
vey our sincere thanks. This book could not
have been published without the cooperation
of Barbara Makinster, Editorial Project
Manager. We wish to express our cordial grati-
tude to Elsevier Inc., Michelle Fisher
(Acquisition Editor), and other editorial staff
for their invaluable supports in organizing the
intelligent editing of the book. We also grate-
fully acknowledge all the permissions we
received for reproducing the copyright materi-
als from different sources. Finally, we cannot
overlook the sacrifices and supports from our
family members during the preparation of the
current book. All our friends, colleagues, and
students who have helped in the process of
editing this book deserve our great apprecia-
tion. Contributing authors, the publishers, and
we, the editors, will be extremely happy if our
endeavor fulfills the needs of the academicians,
researchers, students, pharmaceutical experts,
biomedicine experts, and formulators.
Amit Kumar Nayak1, Amal Kumar Dhara2
and Dilipkumar Pal3
1
Department of Pharmaceutics, Seemanta Institute
of Pharmaceutical Sciences, Jharpokharia, India
2
Department of Pharmacy, Contai Polytechnic,
Govt. of West Bengal, Contai, India 3Department of
Pharmaceutical Sciences, Guru Ghasidas
Vishwavidyalaya (A Central University), Bilaspur,
India
 C H A P T E R
1
Biological macromolecules: sources,
properties, and functions
Amal Kumar Dhara1 and Amit Kumar Nayak2
1
Department of Pharmacy, Contai Polytechnic, Contai, India 2Department of Pharmaceutics, Seemanta
Institute of Pharmaceutical Sciences, Jharpokharia, India
1.1 Introduction
The mystery of life is in biological macromo-
lecules. There are four important classes of bio-
logical macromolecules, viz., carbohydrates,
lipids, proteins, and nucleic acids (Luo, Zhang,
Wu, Liang, & Li, 2020; Zhang, Sun, & Jiang,
2018). Carbohydrates, proteins, and nucleic
acids naturally exist as long chain polymers,
while lipids are smaller and in true sense, these
are all considered as biopolymers (Albertsson,
2019; Teramoto, 2020; Zhang et al., 2018).
Carbohydrates are the storage form of energy
and meet the demand as and when required
(Slavin & Carlson, 2014). Lipids are also stor-
age form of energy and are the important
structural components of the cell membrane
(van Meer, Voelker, & Feigenson, 2008; Zheng,
Fleith, Giuffrida, O’Neill, & Schneider, 2019).
Proteins serve several functions including
structural support, catalyzing important meta-
bolic reactions, signals receiving and transmis-
sion, etc. (Watford & Wu, 2018; Zaretsky &
Wreschner, 2008). Nucleic acids, that is, deox-
yribonucleic acid (DNA) and ribonucleic acid
Biological Macromolecules
DOI: https://doi.org/10.1016/B978-0-323-85759-8.00005-1
(RNA) are responsible for carrying genetic
blueprint and information for protein synthesis
(Minchin & Lodge, 2019; Schwartz, Schwartz,
Mieszerski, McNally, & Kobilinsky, 1991).
Biological macromolecules are abundantly
available in nature and also possess properties
like biocompatibility, environmental friendly,
biodegradability, etc., because of their natural
sources (Chandika et al., 2020; Teramoto, 2020).
Various species of algae have been mentioned
to be used as bioactive compounds and are
also employed as antibacterial agents (Shannon
& Abu-Ghannam, 2016). Various disorders
related to central nervous system, such as
Alzheimer’s disease, Parkinson’s disease, con-
vulsive disorders, etc., are being treated with
the biological macromolecules (Acosta &
Cramer, 2020; Soderquist & Mahoney, 2010;
Zhang et al., 2018). All the biological macromo-
lecules, viz., carbohydrates, lipids, proteins
and nucleic acids, have shown their significant
role in the management of cancer therapy and
have been advocated to be used against vari-
ous cancers like lung cancer, colon cancer,
breast cancer, cervical cancer, etc.
3 © 2022 Elsevier Inc. All rights reserved.
4 1. Biological macromolecules: sources, properties, and functions
(Corn, Windham, & Rafat, 2020; Oana,
Adriana, Mircea, Dragos, & Monica, 2018;
Rodrigues Mantuano, Natoli, Zippelius, &
Läubli, 2020; Sun, Jing, Ma, Feng, & Hu, 2020).
Another important area of research is immuno-
modulators with respect to present SARS-CoV-2
perspective, where the biological macromole-
cules, mainly proteins, play significant role (Ji
et al., 2020). Proteins are associated with the
development process of immune system (Daly,
Reynolds, Sigal, Shou, & Liberman, 1990).
Lipids are also responsible to play key role as
adjuvants for the development of vaccines
(Martinez-Gil, Goff, & Tan, 2018; Schwendener,
2014). Day by day, the incidence of lifestyle
diseases more specifically diabetes, hyperten-
sion, etc., are increasing vertically, where the
roles of biological macromolecules have been
studied and were found to be utilized widely
as antidiabetic agents (Alam, Shafique, Amjad,
& Bin Asad, 2019; Hu, Nie, & Xie, 2018; Rı́os,
Francini, & Schinella, 2015; Yu, Shen, Song, &
Xie, 2018). They cause increase in insulin secre-
tion and thus, reduce the blood glucose level
(Rı́os et al., 2015). Chitosan is a well-known
polysaccharide, which is reported to exhibit
antimicrobial and antidiabetic activities
(Hasnain & Nayak, 2018; Karadeniz & Kim,
2014; Rabea, Badawy, Stevens, Smagghe, &
Steurbaut, 2003). Extensive research is going
on in the area of tissue engineering for the
development of artificial tissue to repair and
replace defective or diseased tissue or organs
(Hasnain, Ahmad, Chaudhary, Hoda, &
Nayak, 2019; Nayak, Ahmed, Tabish, &
Hasnain, 2019; Pal, Saha, Nayak, & Hasnain,
2019). Naturally derived biological macromole-
cules like chitosan, alginate, carrageenan,
ulvan, gelatin, etc., have been used for
bone tissue regeneration (Hasnain, Nayak,
Singh, & Ahmad, 2010; Maity, Hasnain, Nayak,
& Aminabavi, 2021; Nayak, Ahmed, Tabish, &
Hasnain, 2019). Numbers of polysaccharide
have long been used in different types of drug
delivery systems as biopolymeric excipients
I. Background
(Hasnain et al., 2020; Kandar, Hasnain, &
Nayak, 2021; Maity et al., 2021; Nayak &
Hasnain, 2019a, 2019b; Nayak, Hasnain, Dhara,
& Pal, 2021; Pal, Saha, Nayak et al., 2019).
Polysaccharide and proteins are used exten-
sively for the preparation of hydrogels for
drug delivery, tissue regeneration, wound
dressings, etc. (Del Valle, Dı́az, & Puiggalı́,
2017; Nayak & Pal, 2016b; Nayak, Hasnain,
Pal, Banerjee, & Pal, 2020; Pal, Nayak, & Saha,
2019a, 2019b; Ray et al., 2020). Beside drug
delivery, the biological macromolecules have
continuously been used to formulate delivery
carrier-systems for growth factors (Rao, Rekha,
Anil, Lowe, & Venkatesan, 2019; Shariatinia,
2019). Polysaccharides are also employed for
the encapsulation of various bioactive sub-
stances like vitamins and nutraceuticals (Bala,
Singha, & Patra, 2019; Lauro, Amato, Sansone,
Carbone, & Puglisi, 2019). The current chapter
deals with a brief discussion about the sources,
properties, and valuable applications of vari-
ous biological macromolecules like carbohy-
drates, lipids, proteins and nucleic acids.
1.2 Carbohydrates
The most widely found organic compounds
in nature are carbohydrates. These are well-
known as very essential source of life or sus-
taining life itself (Slavin & Carlson, 2014).
Carbohydrates are commonly found in plants,
microorganisms and animal tissues (Werz &
Seeberger, 2005). These are also present in
blood, tissue fluids, etc. (Kilcoyne & Joshi,
2007). Carbon, hydrogen and oxygen are the
three primary elements of molecular structure
of carbohydrates (Luo et al., 2020; Werz &
Seeberger, 2005). These are optically active
polyhydroxy aldehydes or ketones. There are
three major classes of carbohydrates, broadly,
monosaccharides, oligosaccharides and poly-
saccharides (Slavin & Carlson, 2014).
 1.2 Carbohydrates
1.2.1 Monosaccharides
These are generally called simple sugars,
and the most common monosaccharide is glu-
cose. Most of the monosaccharides comprise of
the general formula CnH2nOn (Pigman &
Horton, 1972). The different classes of mono-
saccharides include aldoses (functional group
is aldehyde), and ketoses (functional group is
keto) (Slavin & Carlson, 2014; Werz &
Seeberger, 2005). On the basis of number of
carbon in the sugar, they are also subcategor-
ized into (Shin & Kim, 2013; Slavin & Carlson,
2014):
1. Trioses (containing three carbon atoms in
the sugar), for example, glyceraldehydes
and dihydroacetone,
2. Tetroses (containing four carbon atoms in
the sugar), for example, erythrose and
erythrulose,
3. Pentoses (containing five carbon atoms in
the sugar), for example, ribose and xylulose,
4. Hexoses (containing six carbon atoms in the
sugar), for example, glucose, glactose,
fructose and mannose, and
5. Heptoses (containing seven carbon atoms in
the sugar), for example, sedoheptulose.
Physicochemical properties of monosacchar-
ides: These are soluble in water, sweet in taste
and permeable through plasma membrane.
Monosaccharides react with hydrazine to form
osazones (Pigman & Horton, 1972). They
undergo reduction and form sugar alcohols
(e.g., glucose-sorbitol; fructose-mannitol; galac-
tose-dulcitol; glyceraldehyde-glycerol, etc.). On
oxidation, these produce sugar acids like glu-
conic acid. Monosaccharides play varieties of
important physiological functions (Pigman &
Horton, 1972). These are used for energy pro-
duction in living organisms. The vital compo-
nents of cells are RNA and DNA, which are
composed of ribose and deoxyribose and are
well-recognized as the building blocks of life
(Minchin & Lodge, 2019).
I. Background
5
1.2.2 Oligosaccharides
These yield 2
10 monosachharides on
hydrolysis. On the basis of number of mono-
saccharide units present, these are further sub-
classified into (Shin & Kim, 2013; Slavin &
Carlson, 2014): disaccharides (e.g., sucrose,
maltose, lactose and trehalose), trisaccharides
(e.g., raffinose and maltotriose), etc. These can
exhibit reducing property, when these contain
free aldehyde and/or ketone group, which is/
are not participated in the formation of
linkage.
1.2.3 Polysaccharides
These are formed by uniting monosaccha-
ride or there derivatives. These are joined
together by glycosidic linkage (Maity et al.,
2021). Unlike proteins and nucleic acids, poly-
saccharides exist as both linear as well as
branched polymers. These are colloidal in
nature. Polysaccharides are grouped into two
categories (Shin & Kim, 2013; Slavin & Carlson,
2014):
1. Homopolysaccharides: These yield one type
of monosaccharides on hydrolysis, for
example, starch, cellulose, glycogen, etc.
2. Heteropolysaccharides: These yield two or
more different type of monosaccharides on
hydrolysis, for example, hyaluronic acid,
heparin, chondriotin sulfate, etc.
Some important homopolysaccharides are
described here:
1. Starches—These contain several units of
glucose joined in α-1, 4-linkages and are
well-known as examples of
homopolysaccharides (Nayak & Pal, 2017).
In plants, it is the storage form of
carbohydrates. Different parts of the plants
are rich in starches like tubers, roots,
vegetables, cereals, etc. (Nayak & Pal, 2017;
Nayak, Bera, & Hasnain, 2020). In higher
6 1. Biological macromolecules: sources, properties, and functions
animals, starches are the most important
source of food. These consist of two types of
molecules (Fig. 1.1): (A) linear and water
soluble component, e.g., amylose and (B)
branched water insoluble, e.g., amylopectin.
Commercially, starch is produced mostly
from corn, but wheat starch, potato starch,
and tapioca starch are also used (Nayak
et al., 2020).
2. Cellulose—It is the chief constituent of
fibrous parts of the plants and consequently,
is the most abundant organic material
occurring in nature (Pal et al., 2019b). It is
made up of long chains of β D-glucose
molecules linked by 1, 4-linkages (Fig. 1.2). It
serves as bulk forming agent of the food.
Undigested cellulose increases the bulk of
feces and helps in the evacuation of bowels.
Cellulose exhibits some of important
FIGURE 1.1 Molecular structure of starch: (A) linear and water soluble component: amylose and (B) branched water
insoluble: amylopectin.
I. Background
properties like low density, flexibility, high
strength, biocompatibility, biodegradability,
etc., which suggest for biomedical
applications (Hasnain et al., 2020; Kandar
et al., 2021). In traditional healthcare,
cellulosic biomaterials play an important role
and recently, some significant areas of
application are being explored with the uses
of cellulose like drug delivery (Hasnain et al.,
2020; Kandar et al., 2021; Pal et al., 2019b),
tissue engineering (Hasnain, Nayak, Singh, &
Ahmad, 2010; Murizan, Mustafa, Ngadiman,
Mohd Yusof, & Idris, 2020), management of
wound (Alven & Aderibigbe, 2020), etc. By
using quaternary ammonium salt the surface
of cellulose nanocrystals (CNC) is modified,
which can inhibit the growth of Staphylococcus
aureus and Escherichia coli (Tavakolian, Jafari,
& van de Ven, 2020).
 1.2 Carbohydrates
FIGURE 1.3 Molecular structure of dextran.
3. Dextran—It is a highly branched polymer of
glucose, produced by yeast or bacteria
(Chen, Huang, & Huang, 2020; Huang &
Huang, 2018). The linear chain dextran
molecular structure are formed by 1, 6-α
glycosidic linkages (Fig. 1.3). Dextran occurs
in honey, maple syrup, etc. It is used as
plasma substitutes as it retains water in
circulation for longer period, when
administered intravenously (i.v.). Dextran
and its derivatives are being used to
formulate nanocarriers for advanced drug
delivery applications (Huang & Huang,
2018).
I. Background
7
FIGURE 1.2 Molecular
structure of cellulose.
4. Pectins—These form gel with sugar
solutions. In nature, pectins are usually
found in pulps and peels of citrus fruits,
apple pomaces, beet roots, etc. (Nayak &
Pal, 2016a). Chemically pectins are
polysaccharide of galacturonic acid,
galactose, and arabinose (Hasnain et al.,
2020; Kandar et al., 2021). Molecular
structure of pectin is presented in Fig. 1.4.
Pectins have been found to possess
beneficial biological activities, like
antioxidant, antiinflammatory, antibacterial,
immune regulation, and anticoagulation
activities (Rascoń-Chu, Gomez-Rodriguez,
Carvajal-Millan, & Campa-Mada, 2019).
Biomedical applications of pectins include
tissue engineering, drug delivery, wound
healing and gene delivery (Hasnain et al.,
2020; Kandar et al., 2021; Maity et al., 2021;
Nayak et al., 2019, 2021; Rascoń-Chu et al.,
2019).
5. Gum acacia or Gum Arabic—It is a plant-
derived gum containing hexoses or pentoses
or both. It is extensively used in
pharmaceutical, food and cosmetic
industries (Nayak, Das, & Maji, 2012). It is
an effective and useful excipient for the
preparation of nanomaterials for drug
delivery (De, Nayak, Kundu, Das, &
Samanta, 2021).
6. Alginates—These consist of linear polymer
of β (1-4)-linked D-mannuronic acid
(M-unit) and α (1-4)-linked L-guluronic
8 1. Biological macromolecules: sources, properties, and functions
FIGURE 1.4 Molecular structure of pectin.
acid (G-unit) (Hasnain et al., 2020; Kandar
et al., 2021; Nayak et al., 2021). Molecular
structure of pectin is presented in Fig. 1.5. It
is processed from marine algae and giant
kelp as raw materials. These are widely
used as thickener, emulsifier, stabilizer, etc.
(Kandar et al., 2021). Alginate based drugs
are effectively used for antimicrobial as well
as antiviral therapy (Szekalska, Pucilowska,
Szymańska, Ciosek, & Winnicka, 2016). The
alginate film with EDTA exhibited stronger
antimicrobial effects against Gram-negative
bacteria, especially, in case of processed
food packaging (Senturk Parreidt, Müller, &
Schmid, 2018). Structural modifications of
alginates can easily be made by using
crosslinkers, improvise the mechanical
strength and cell affinity and was widely
I. Background
FIGURE 1.5 Molecular structure of alginate.
used in the biomedical applications mainly
in drug delivery and tissue regeneration
(Malakar, Nayak, Jana, & Pal, 2013; Malakar,
Nayak, & Das, 2013).
7. Chitosan—It is a cationic natured
carbohydrate polysaccharide, extracted by
deacetylation of chitin (Hasnain & Nayak,
2018). It is reported to show various
biological properties including antidiabetic,
antioxidant, immune-enhancing,
antimicrobial as well as anticancer activities
(Hasnain & Nayak, 2018; Rabea et al., 2003;
Rı́os et al., 2015). Chitosan is very much
effective in the formulation of insulin with
controlled delivery functionality at the target
site (Barbosa et al., 2020). Carboxymethyl-
hexanoyl derivative and polyethylene glycol-
trimethyl complexes of chitosan have been
 1.3 Lipids
found to possess fat-lowering and fat-
preventing properties. Chitosan-based
collagen complex sponges showed
effectiveness in the healing of diabetic
wounds (Wang et al., 2008). Chitosan and its
derivatives are being extremely used in many
biomedical applications, such as drug
delivery, tissue engineering, wound dressing,
orthopedics, etc. (Hasnain et al., 2020;
Hasnain, Ahmad, Chaudhary, Hoda, &
Nayak, 2019; Hasnain, Nayak, Singh, &
Ahmad, 2010; Kandar, Hasnain, & Nayak,
2021; Maity, Hasnain, Nayak, & Aminabavi,
2021; Nayak, Ahmed, Tabish, & Hasnain,
2019; Pal, Saha, Nayak, & Hasnain, 2019).
8. Agar—It is a natural polysaccharide
obtained from seaweeds. It is a sulfuric acid
ester of a complex galactose polysaccharide
(Kandar et al., 2021). It is nondigestible
material and is used as a bulk laxative.
Recent years, a number of biocompatible
agar-based composite has been formulated
for their potential applications in biomedical
fields including drug delivery and tissue
engineering applications (Kandar et al.,
2021; Nayak, Alkahtani, & Hasnain, 2021;
Shah et al., 2019).
TABLE 1.1 Sources and functions of various polysaccharides.
Polysaccharides Source type
Cellulose Plants
Starches Plants
Pectins Plants
Carrageenan Microorganism
Alginate Microorganism
Hyaluronan Animals
Heparin Animals
Chondroitin sulfate Animals
Chitin and chitosan Animals
I. Background
9
9. Glycogen—This is also known as animal
starch, as it is a principal polysaccharide
occurring in animal tissues, specifically in
liver and muscle (Roach, Depaoli-Roach,
Hurley, & Tagliabracci, 2012). Glycogen is
the storage form of energy release, quickly,
when needed (Kreitzman, Coxon, & Szaz,
1992). Similar to starch, this is also
composed of glucose units united by 1, 4-
linkages and branches arising by 1, 6-
linkages.
Sources and functions of various polysac-
charides are listed in Table 1.1.
1.3 Lipids
Lipids are heterogeneous group of organic
compounds, related either actually or poten-
tially, to the fatty acids (Pandey & Kohli, 2018).
They are poorly soluble in water and soluble in
nonpolar solvents like chloroform, benzene,
petroleum ether, etc. In our body, lipids are an
integral part of the cell membrane structure,
metabolic fuel and storage form of energy (van
Meer et al., 2008; Zheng et al., 2019). Lipids act
Functions
Cell structure and food additives
Storage and drug adjuvants
Food additives
Food additives
Drug adjuvant
Animal tissue structure, therapeutic agents
Animal tissue structure, therapeutic agents
Animal tissue structure
Tissue scaffolds
10 1. Biological macromolecules: sources, properties, and functions
as mechanical, thermal and electrical insulators
(Pandey & Kohli, 2018). Lipids are usually clas-
sified as follows:
1.3.1 Simple lipids
These are esters of fatty acids with certain
alcohols, generally glycerol. According to
nature of alcohols, these are (Vance & Vance,
2002):
1. Fats and oils: Ester of fatty acids with
glycerol. These are also known as natural fat
or triglyceride or triacylglycerol. At room
temperature when these are solid known as
fat and when liquid these are known as oil.
2. Waxes: These are esters of fatty acid with
higher molecular weight monohydric
alcohol.
1.3.2 Compound or conjugate lipids
These are ester of fatty acids containing
groups, in addition to an alcohol and the fatty
acids. These are further classified as (Vance &
Vance, 2002):
1. Phospholipids: These contain fatty acids,
glycerol, a phosphoric acid residue and
sometimes a nitrogenous base. They are
subdivided as:
a. Phosphotidic acids—on hydrolysis, these
produce one molecule each of glycerol
and phosphoric acid with two molecules
of fatty acids.
b. Lecithins—contain glycerol, fatty acid,
phosphoric acid and the nitrogen base
choline. These are widely distributed in
different animal tissues including brain,
liver, blood, cardiac muscles, etc., and also
found in plant seeds. Lecithins are used as
emulsifying and smoothing agents in food
industry (Robert, Couëdelo, Vaysse, &
Michalski, 2020). Lecithins have been
mentioned to be used for the
I. Background
development of nanocarriers for drug
delivery (Das, Sen, Maji, Nayak, & Sen,
2017; Malakar, Sen, Nayak, & Sen, 2012).
c. Cephalins—similar in structure with
lecithin but the base is ethanolamine.
These are found in brain, liver, cardiac
muscles, erythrocytes, etc.
d. Plasmalogens—found in brain, cardiac
muscles, erythrocytes, etc.
e. Sphingomyelins—on hydrolysis, these
give a single fatty acid, a nitrogen base
sphingosine, phosphoric acid and choline
but no glycerol. These participate in
different signaling pathways.
2. Glycolipids: These contain sphingol, a
carbohydrate (galactose), and fatty acid.
Large amount of glycolipids are present in
the white matter of brain and in the myelin
sheath of nerves (Willison, 2018).
3. Sulpholipids: Lipid material containing
sulfur has long been known to be present in
the different tissues like liver, kidneys,
brain, etc. It is found in the white matter of
the brain.
4. Lipoproteins: These are composed of
lipid material bound to the protein. The
lipid of lipoproteins mainly consists of
cholesterol esters and phospholipids (such
as stearic, palmitic, and oleic acids)
(Schumaker & Adams, 1969). These are
found in plasma and the four important
lipoproteins are chylomicrons, pre-
β-lipoprotein, β-lipoprotein and
α-lipoprotein. Hyperlipoproteinemia is
clinically significant, nowadays, as
lipoproteins are directly related with
atherosclerotic cardiovascular disease
(Arnao, Tuttolomondo, Daidone, &
Pinto, 2019).
1.3.3 Derived lipids
These are substances derived by hydrolysis
of simple or compound lipids.
 1.4 Proteins 11
FIGURE 1.6 (A) Cyclopentano perhydro phe-
nantherene ring system in steroids, and (B) molecu-
lar structure of cholesterol.

1. Steroids: These are abundantly found in carrier systems, such as liposomes, transfero-
nature. Steroids are derivative of complex somes, solid lipid nanoparticles, lipid nanos-
ring system named as cyclopentano tructures, etc.
perhydro phenantherene (Fig. 1.6A). The
important classes of steroids include sterols,
bile acids, sex hormones, adrenal cortical
hormones, Vitamin D, saponins and cardiac
1.4 Proteins
glycosides (Cole, Short, & Hooper, 2019).
Proteins constitute a diverse, heterogeneous
2. Sterols: Cholesterol is a well-known sterol
class of macromolecules and these may be said
(Fig. 1.6B). It is a white and waxy substance,
as the essence of life processes (Zaretsky &
widely distributed in all cells of the body,
Wreschner, 2008; Zhang et al., 2018). These are
particularly in nervous tissue. Cholesterol is
high molecular weight extremely complex
the precursor of bile salts, adrenocorticoids,
polymers of amino acids (Watford & Wu,
sex hormones, Vitamin D and cardiac
2018). In addition to carbon, hydrogen, oxygen
glycosides (Schade, Shey, & Eaton, 2020).
atoms, the molecular structure of proteins con-
Eicosapentaenoic acid (EPA) and
tains nitrogen and sometimes sulfur, phospho-
docosahexaenoic acid (DHA) play important
rus, iron, copper, manganese, iodine, zinc, and
roles with respect to immune functions,
other elements. The amino acids of proteins are
neurological and cardiovascular disorders
joined together with the help of peptide bonds
(Ochi & Tsuchiya, 2018).
(
CO
NH
). The common structure of pro-
Basic functions of different lipids are listed tein is presented in Fig. 1.7. These exhibit varie-
in Table 1.2. Recent studies have showed the ties of functions in cells by acting as structural
efficacy of various lipid-based drug delivery materials, carrier molecules, enzymes,

I. Background
12 1. Biological macromolecules: sources, properties, and functions

TABLE 1.2 Basic functions of lipids.

Type of lipids Functions

Fatty acids Precursor of triglyceride and source of energy

Triglyceride Storage of energy, thermal insulation and protection, binding of organs together
Cholesterol Component of cell membranes and also the Precursor of different steroids
Phospholipids Structural component of cell membranes and helps in digestion of fat
Bile acids Helps in fat digestion and absorption of nutrients
Eicosanoids Chemical messenger between cells

Dietary fat Carry lipid soluble Vitamins (A, D, E and K)

FIGURE 1.7 Common structure of protein.

lubricants, etc. (Zaretsky & Wreschner, 2008).
Proteins derived from different sources (ani-
mals and plants) have been used for the isola-
tion of peptides, and exhibited different
biological activities for humans (Daly et al.,
1990; Nayak, 2010). Proteins are classified in
three groups, namely simple proteins, conju-
gated proteins and derived proteins (Watford
& Wu, 2018).
1.4.1 Simple proteins
Upon hydrolysis, these types of proteins
yield only amino acids or their derivatives
(Murray, Harper, Granner, Mayes, & Rodwell,
2006; Watford & Wu, 2018). Simple proteins
are further classified into albumins, globulins,
glutelins, prolamins, albuminoids (scleropro-
teins), histones and protamines.
1. Albumin: These are soluble in water,
coagulated by heat, and precipitated by
saturated salt solution. Examples are
lactalbumin, serum albumin, egg albumin,
myogen of muscle, etc.
2. Globulin: These are soluble in dilute solution
of strong acids and bases and get coagulated
by heat. Examples are serum globulin,
ovoglobulin, myosin of muscle, etc.
3. Glutelin: These are soluble in dilute acids
and alkalis and get coagulated by heat.
Examples are glutenin from wheat and
oryzenin from rice, etc.

I. Background
 1.4 Proteins
4. Prolamines: These are soluble in 70%
80%
alcohol and insoluble in water, absolute
alcohol and other neutral solvents.
Examples are zein (corn), hordein (barley),
gliadin (wheat), etc.
5. Albuminoids (Screlroproteins): Albuminoids
are insoluble proteins and form supportive
tissues. These are animal proteins found in
hair, nails, horns and hooves. Examples are
keratin, collagen, gelatin, etc.
6. Histones: These are soluble in water, very
dilute acids and salt solutions. These are not
conjugated by heat and contain basic amino
acids. Examples include nucleic acids.
7. Protamines: These are the simplest of
proteins and are basic polypeptides, soluble
in water and ammonium hydroxides. These
are not conjugated by heat. Examples
include salmine (salmon sperm), clupeine
(herring sperm), etc.
1.4.2 Conjugated proteins
These contain simple protein combined with
nonprotein prosthetic group (Murray et al.,
2006). These include: (1) nucleoproteins (2) pro-
teoglycans and glycoproteins (3) chromopro-
teins (4) phosphoproteins (5) lipoproteins and
(6) metalloproteins (Murray et al., 2006;
Watford & Wu, 2018).
1. Nucleoproteins: These proteins are
composed of simple proteins with nucleic
acids as prosthetic group. In nucleoproteins,
protein moiety is usually a basic protein like
protamine and histone. Examples include
chromosomal proteins and some glandular
proteins.
2. Proteoglycans and glycoproteins: These
proteins contain carbohydrates as prosthetic
group like hyaluronic acid and chondroitin
sulpahte. These are mainly found in blood
plasma, gastric and salivary mucine,
immunoglobulins, human chorionic
gonadotropins, etc.
I. Background
13
3. Chromoproteins: These are composed of
simple proteins with chromotropic group as
prosthetic group. Examples include
hemoglobin (prosthetic group is heme),
flavoproteins (prosthetic group is
riboflavin), cytochrome (prosthetic group is
heme), etc.
4. Phosphoproteins: These are composed of
proteins and phosphoric acid as the
prosthetic group. Caesin (milk protein) and
vitelline (egg yolk protein) are the important
examples of this group.
5. Lipoproteins: These proteins are the
combination of proteins and lipids (fatty
acid, lecithin, cephalin, etc.) as prothetic
group. Lipoproteins occur in blood, cell
nuclei, milk, cell membranes, egg yolk, etc.
6. Metalloproteins: These are compounds of
proteins and some metals (such as iron,
cobalt, zinc, manganese, copper and
magnesium). Examples are ferritin,
ceruloplastin, carbonic anhydrase, etc.
1.4.3 Derived proteins
These are formed from simple and conjugate
proteins by denaturation or partial hydrolysis
(Murray et al., 2006). They are of two types (1)
denatured or primary derived proteins and (2)
secondary derived proteins (Murray et al.,
2006; Watford & Wu, 2018).
1. Denatured or primary derived proteins:
These proteins may be of different types.
a. Proteans—derived in the early stages of
protein hydrolysis by water, dilute acids
or alkalis or enzymes. Examples include
fibrin from fibrinogen, myosan from
myosin and edestan from edestin.
b. Metaproteins—derived by further
hydrolysis by stronger acids or alkalies,
which are insoluble in very dilute acids
and alkalis. Examples of such proteins
include acid metaproteins and alkali
metaproteins.
14 1. Biological macromolecules: sources, properties, and functions

c. Coagulated proteins—derived by the Bioactive proteins obtained from legumes have

action of heat, ultraviolet (UV)-rays, X-
rays, very high pressure, mechanical
shaking, etc. Examples are coagulated
albumin, cooked meat, etc.
2. Secondary derived proteins: Progressive
hydrolysis of peptide bond caused
breakdown of proteins into smaller
molecules, which include (Murray et al.,
2006):
a. Proteoses—formed by the action of
pepsin and trypsin,
b. Peptones—produced by further
hydrolytic decomposition and
c. Peptides—composed of two or more
amino acids (such as dipeptides, and
polypeptides).
Plethora of proteins and peptides with vari-
eties of biological activities has already been
identified (Nayak, 2010). Some of the proteins
and peptides exhibit bioactivities like antioxi-
dant, antihypertensive, antibiotics, immuno-
modulatory, anticancer activities, etc.
(Giromini, Cheli, Rebucci, & Baldi, 2019).
been found beneficial in the prevention of obe-
sity and type-II diabetes (Moreno-Valdespino,
Luna-Vital, Camacho-Ruiz, & Mojica, 2020).
Anticancer activities are also demonstrated by
some important biological proteins like lectins,
glycoproteins, etc. (Laaf, Bojarová, Pelantová,
Křen, & Elling, 2017; Rodrigues Mantuano
et al., 2020; Singh, Kaur, & Kanwar, 2016).
Gelatin obtained from animal collagen, either
acid or alkali treated, is used in bone tissue
engineering as it is biocompatible, low immu-
nogenic and biodegradable (Hasnain et al.,
2019). Pharmacological effects of bioactive pro-
teins/peptides along with their sources are
listed in Table 1.3.
1.5 Nucleic acids
Nucleic acids are nonprotein nitrogenous
macromolecules, in which the nucleotides
remain linked to each other by phosphodiester
bonds in-between the 30 and 50 position of the

TABLE 1.3 Pharmacological effects of bioactive proteins/peptides along with their sources.
Bioactive proteins/
peptides Sources Pharmacological effects

Fibrinolytic Eisenia fetida Antitumor activity against several hepatoma cell lines, in vitro and in vivo (Chen
enzymes (earthworm) et al., 2007)
Hirudin Hirudo Anticoagulation activity through inhibition of thrombin activity (Markwardt, 2002)
medicinalis
Cordymin Cordyceps Antifungal activity (Wong et al., 2011), anticancer and inhibitory effect on HIV-1
militaris reverse transcriptase (Wong et al., 2019), antiinflammatory and antinociceptive
activities (Qian, Pan, & Guo, 2012)
Lectin Cordyceps Hemagglutinating activity and mitogenic activity (Wong, Wang, & Ng, 2009)
militaris
Ginkbilobin Ginkgo biloba Antifungal activity (Wang & Ng, 2000)
seeds
Dioscorin Dioscorea batatas Trypsin inhibitory activities (Hou et al., 1999)
Trichosanthin Trichosanthes Anti-HIV activity (Zhao, Ben, & Wu, 1999) and antiviral activity against hepatitis B
kirilowii virus (Wen et al., 2015)

I. Background
 1.5 Nucleic acids
sugars (Minchin & Lodge, 2019; Nelson & Cox,
2005). A nucleotide is composed of a pentose, a
phosphate and a nitrogen base. The nitrogen
base may be a purine or a pyrimidine. In case
of RNA and DNA, the pentose is ribose and
deoxyribose, respectively (Brosius & Raabe,
2016; Schwartz et al., 1991). Adenine and gua-
nine are the major purine bases (others are
methyladenine, methylguanine, hypoxanthine,
etc.) whereas cytosine, uracil and thymine are
the major pyrimidine bases (others include 5-
methylcytosine, 5, 6-dihydrouracil, etc.) of
nucleic acids (Brosius & Raabe, 2016; Schwartz
et al., 1991). Various functions of nucleic acids
are (Minchin & Lodge, 2019; Nelson & Cox,
2005):
1. Nucleic acids direct the metabolism process
of the cell throughout the life
2. Synthesis of protein is directed by nucleic
acids
3. They regulate the synthesis of enzymes
4. They play important role in the transfer of
genetic information from one offspring to
another
5. Nucleic acids contribute essential substances
of the genes and the apparatus by which the
genes act
6. Nucleic acids are intimately involved with
the varieties of disease like cancers, etc. and
are major areas for research
1.5.1 Nucleotides
When the phosphate diester bond gets
hydrolyzed, the monomeric nucleic acids are
separated which consist of nitrogenous base, a
sugar and a phosphate, and that unit is called
nucleotide (Nelson & Cox, 2005; Zaharevitz
et al., 1992). According to the presence of
ribose or deoxyribose, these may be ribonu-
cleotides or deoxyribonucleotides, respectively.
Nucleotides carrying more than one phosphate
group are called higher nucleotides, for exam-
ple, adenosine triphosphate (ATP), adenosine
I. Background
15
diphosphate (ADP), guanosine triphosphate
(GTP), guanosine diphosphate (GDP), cytidine
triphosphate (CTP), cytidine diphosphate
(CDP), uridine triphosphate (UTP), etc.
(Murray et al., 2006).
1.5.2 Nucleosides
It is a structural subunit of nucleic acids. In
living cell, nucleoside is the heredity control-
ling component (Murray et al., 2006; Nelson &
Cox, 2005). When the ester bond between the
sugar and the phosphate group in a nucleotide
is hydrolyzed, a fragment consists of nitroge-
nous base and a sugar moiety is obtained
which is called as nucleoside. Sugar moiety in
nucleoside is either ribose or deoxyribose,
whereas nitrogenous bases consist of either a
pyridine, that is, cytosine, thymine, or uracil or
a purine, that is, adenine or guanine (Nelson &
Cox, 2005).
1.5.3 DNA
DNA is a biological macromolecule where
genetic information of cell is confined, which is
known as genome of the cell (Nelson & Cox,
2005; Watson & Crick, 1953). It is a polymer of
deoxyribonucleotides. It occurs in chromo-
somes, mitochondria and chloroplasts. The
chemical nature of monomeric units of DNA is
deoxyadenylate, deoxyguanylate, deoxycytidy-
late and thymidylate (Watson & Crick, 1953).
The monomeric units are held in polymeric
form by 30 , 50 -phophodiester bridges constitut-
ing a single strand (Murray et al., 2006). The
genetic information resides in the sequence of
the monomeric unit. The polymer possesses a
polarity, that is, one end has a 50 -hydroxyl or
phosphate terminus while other has a 30 -phos-
phate or hydroxyl moiety. In DNA, the concen-
tration of adenosine nucleotide equals to
thymidine and the concentration of guanosine
nucleotide equals to cytosine nucleotide
16 1. Biological macromolecules: sources, properties, and functions

(Nelson & Cox, 2005; Watson & Crick, 1953).
The secondary structure of DNA consists of a
double stranded helix (Watson & Crick, 1953).
The two strands of right handed DNA mole-
cules are held by hydrogen bonds. Each strand
is again compactly held by hydrophobic forces
between the rings of its consecutive bases. The
pairing between the purine and pyrimidine
nucleotides on opposite strands is (Chang,
2017) specific and dependent upon hydrogen
bonding of adenine (A) residue with thymine
(T) residue and guanine (G) with cytosine (C)
residue (Malhotra & Ali, 2018; Watson & Crick,
1953). Schematic representation of the structure
of DNA with its nitrogenous bases is presented
in Fig. 1.8 (right-hand side).
Important biological roles of DNA are
(Nelson & Cox, 2005; Pisetsky, 2017; Watson &
Crick, 1953):
1. The function of DNA is to act as a storage
house of genetic information and to control
the synthesis of protein in the cell.
2. Cell replication—Hereditary characteristics
are passed on to daughter cells through
replication of DNA.
3. Control protein synthesis.
4. Transcription and translation.
1.5.4 RNA
There are three types of RNA known to exist
(Brosius & Raabe, 2016):
1. Messenger RNA (mRNA)
2. Transfer RNA (tRNA)
3. Ribosomal RNA (rRNA)
These are polymer of purine and pyrimidine
ribonucleotides linked together by phophodie-
ster bonds (Nelson & Cox, 2005). Schematic
representation of the structure of RNA with its
nitrogenous bases is presented in Fig. 1.8 (left-
hand side). Major nucleotides in RNA are
adenylic, guanylic, cytidylic and uridylic acids.
However, thymine is absent except in tRNA.

FIGURE 1.8 Schematic

representation of the structure
of RNA (left-hand side) and
DNA (right-hand side) with its
nitrogenous bases (Malhotra &
Ali, 2018). Source: With permis-
sion, Copyright r 2018 Elsevier
Inc.

I. Background
 1.5 Nucleic acids
RNA is distributed throughout the cell, most of
which remains present in cytoplasm as soluble
and rRNA, but about 10% is found in nucleus
with very small quantities being also present in
the mitochondria (Higgs & Lehman, 2015;
Nissen et al., 2000).
1. Messenger RNA (mRNA): These are
homogenous in size and stability.
Amongst all RNAs, mRNAs exhibit
highest molecular weight (Sergeeva,
Koteliansky, & Zatsepin, 2016). An mRNA
carries adenine, guanine, cytosine and
uracil as the major bases along with some
minor bases, such as methylpurines and
methylpyrimidines (Guan & Rosenecker,
2017). mRNAs give signal for the
synthesis of very important substances
like the enzymes, the proteins, a variety
of polypeptide hormones, etc. (Guan
& Rosenecker, 2017; Sergeeva
et al., 2016).
2. Transfer RNA (tRNA): This consists of
approximately 75 nucleotides and generated
by nuclear processing of precursor molecule
(Balatti, Pekarsky, & Croce, 2017; Phizicky &
Hopper, 2010). It serves as an adapter
molecule for the translation of information
in sequence of nucleotides of mRNA into
specific amino acids. tRNA is participated in
protein synthesis (Phizicky & Hopper, 2010).
Beside the presence of regular bases, that is,
adenine, guanine, uracil and cytosine, tRNA
has been found to contain some very
unusual bases like ribothymidine,
dihydrouracil, inosine, dihydrouridine
(DHU), pseudouridine, etc., which possess
an unusual linkage in-between the sugar
ribose and the base (Higgs & Lehman, 2015;
Nelson & Cox, 2005). All tRNA molecules
consist of an ACC sequence at the 30 termini.
It is through an ester bond to the 30 -
hydroxyl group of the adenosyl moiety that
the carboxyl groups of amino acids are
attached (Phizicky & Hopper, 2010). The
I. Background
17
anticodon group at the end of base paired
stem recognizes the triplet nucleotide or
codon of the template mRNA. The DHU
loop helps to recognize the specific enzyme
which activates the specific amino acids.
The Thymidine-pseudouridine cytidine
binds the tRNA in ribosomes for protein
synthesis (Phizicky & Hopper, 2010).
3. Ribosomal RNA (rRNA): It constitutes
nearly 50%
60% of the total RNA of the cell
and is single stranded fibrous molecules
which are highly elongated (Nelson & Cox,
2005; Urlaub, Kruft, Bischof, Müller, &
Wittmann-Liebold, 1995). An mRNA carries
adenine, guanine, cytosine and uracil as the
major bases along with some minor bases
such as methylpurines and
methylpyrimidines. One or more segments
of mRNA strand carry the genetic code or
message, which is translated into the
primary structure of a protein. Each genetic
code consists of many consecutive
nucleotide triplets called codons, each of
which helps to incorporate specific amino
acids in the peptide being synthesized
(Higgs & Lehman, 2015).
Nucleic Acids, that is, DNA and RNA are
significantly employed as biomedicine for the
management of varieties of physiological con-
ditions (Minchin & Lodge, 2019). In a study, it
was observed that chitosan nanoparticles
loaded with probiotic DNA showed hypogly-
cemic activity (Kaur, Bhatia, Sethi, Kaur, &
Vig, 2017). Antidiabetic activity has been
reported by some other researchers by combin-
ing of berberine and noncoding RNA (Chang,
2017). Floxuridine, a cytotoxic nucleoside ana-
log, is a very good anticancer drug and it can
be incorporated into DNA strands by synthesis
or incorporated into RNA by transcription (Ma
et al., 2018). This can be used as a real nucleo-
side. DNases II of tumor cells hydrolyze the
nucleotide strands and cytotoxic drug is
released.
18 1. Biological macromolecules: sources, properties, and functions
1.6 Conclusion
Biological macromolecules are large cellular
components abundantly obtained naturally
and are responsible for varieties of essential
functions for the growth and survival of living
organisms. Biological macromolecules play an
important role in the biomedical and related
fields. These possess some favorable character-
istics, such as good biocompatibility, excellent
biodegradability, desired mechanical strength,
better bioavailability, etc. These exhibit various
bioactivities like anticancer, antidiabetic, anti-
microbial, antioxidant, immunomodulatory,
etc. Important carbohydrates like alginate, chit-
osan, pectin, starches, carrageenan, fucoidan,
etc., are used commercially. Proteins (polymer
of amino acids) and lipids are being exten-
sively used in materials sciences as well as in
biomedical field. Carbohydrates, lipids, pro-
teins, and/or nucleic acids can modulate the
pathophysiology of neurodegenerative disor-
ders/diseases.
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 C H A P T E R
2
Structure activity relationship of
biological macromolecules
Aurelie Sarah Mok Tsze Chung, Yong Kiat Teo, Wai Teng Cheng
and Joash Ban Lee Tan
School of Science, Monash University Malaysia, Bandar Sunway, Malaysia
2.1 Introduction
Biological macromolecules are naturally
occurring large cellular compounds that can be
generally categorized into four major classes:
proteins, carbohydrates, lipids, and nucleic
acids. Apart from their ability to carry out a
diverse range of physiological functions for the
growth and survival of living organisms, many
biological macromolecules also possess various
bioactivities, including antimicrobial, antioxi-
dant, antitumor, antiviral, antiinflammatory,
antiproliferative, and hypoglycemic activities
(Shi, 2016). Although bioactivity research has
focused heavily on small molecules, there has
nevertheless always been an interest in the use
of macromolecules as drug candidates. These
large compounds may hold certain advantages
over small molecule drugs. For instance, the
structural complexity of some biological
macromolecules allows for relatively higher
specificity, which may lower the risk of sys-
temic adverse effects (Atyabi, Zahir, Khonsari,
Shafiee, & Mottaghitalab, 2017; He, Dong,
Biological Macromolecules
DOI: https://doi.org/10.1016/B978-0-323-85759-8.00002-6 23
Gong, Wang, & Yang, 2010; Mitragotri, Burker,
& Langert, 2014). Higher specificity may also
be associated with higher potency, where the
desirable therapeutic effect can be reached
with a low dose of the macromolecular drug
(Mitragotri et al., 2014). Moreover, advances in
synthetic chemistry and molecular biology
approaches have further enabled the mass pro-
duction of many biomacromolecules (He et al.,
2010; Tripathi & Shrivastava, 2019).
Like most compounds, the functions and
bioactivities of biomacromolecules are often
influenced by their corresponding molecular
structures. As such, structure activities rela-
tionship (SAR) studies are one of the most
actively pursued areas of molecular biology
and biochemistry. With a growing arsenal of
imaging and visualization technologies, molec-
ular structures can now be elucidated more
readily (Maveyraud & Mourey, 2020; Olson,
2018). Conversely, the real challenge lies in
comprehensively describing the influence of
molecular structure on the bioactivity, and
how it pertains to the mechanisms of action for
© 2022 Elsevier Inc. All rights reserved.
24 2. Structure activity relationship of biological macromolecules
these biomacromolecules. A better understand-
ing of this SAR would also allow for the bio-
logical properties of newly discovered
compounds to be inferred from those of similar
existing compounds whose risks have already
been evaluated (McKinney, Richard, Waller,
Newman, & Gerberick, 2000), and better-
inform future design of structural analogs or
derivatives. Therefore, a better understanding
of SAR may accelerate the prototyping stages
and shorten the time of development process,
thereby reducing costs (Guha, 2013; Weida,
William, Leming, Hong, & Roger, 2003).
Moreover, this knowledge may allow for the
designing of synthetic derivatives with
improved pharmacokinetics and pharmacody-
namics (Guha, 2013).
Given the extensive number of bioactive
macromolecules that exist, it would be impos-
sible to discuss all of them within a single
chapter. Instead, this chapter describes several
macromolecules as examples to demonstrate
the relationship between structure and their
various bioactivities, be it antimicrobial, antiox-
idant, or antitumor activities.
2.2 Enzymes as bioactive proteins
The proteins have been extensively studied
in recent decades for their remarkable broad
scope of bioactivities and health benefits,
including antioxidant, antimicrobial, antiin-
flammatory, antitumour, anti-HIV and wound
healing activities (Jakubczyk, Karas,
Rybczynska-Tkaczyk, Zielinska, & Zielinski,
2020; Łojewska et al., 2020; Moghadam, Niazi,
Afsharifar, & Taghavi, 2016; Peng et al., 2021;
Tao, Cai, Wang, Zuo, & He, 2021). They are the
most functionally versatile and abundant bio-
logical macromolecules omnipresent in living
organisms, responsible for a wide range of cel-
lular functions. Proteins are made up of differ-
ent monomers known as amino acids. Each
amino acid consists of the same basic structure:
I. Background
a central carbon atom bonded to a carboxyl
group (2COOH), an amino group (2NH2) and
a side chain which can harbor diverse func-
tional R-groups (Littlechild, 2013). Based on
the various interactions between the amino
acids, the proteins may hold up to four organi-
zational levels and acquire a three-dimensional
molecular shape (Littlechild, 2013). The compo-
sition and sequence of amino acids, together
with an array of R-groups and the inner
dynamic folds, thus determine the overall pro-
tein structure while also contributing to their
chemical properties like solubility, reactivity
and stability, amongst many others (Hvidsten
et al., 2009). As such, the functions and bioac-
tive properties of each protein are greatly
dependent on its three-dimensional structure.
The vast diversity of different sequences
and structures allows proteins to exhibit a
broad range of biological functions and bioac-
tive properties. At present, over 150,000 protein
structures have been recorded in the Protein
Data Bank (PDB) (Guzenko, Burley, & Duarte,
2020). Interestingly, over the course of evolu-
tion, most sequences essential for a given func-
tion are usually conserved, thus facilitating the
identification of many bioactive protein fami-
lies (Jensen, Ussery, & Brunak, 2003). Besides
that, although proteins are considered as
macromolecules, shorter peptides consisting of
only a few amino acids may still exert a bioac-
tive effect (Newstead, Varjonen, Nuttall, &
Paterson, 2020). Usually, peptides with less
than 50 amino acids are referred as small pro-
teins or short peptides (Chen & Lu, 2020; Storz,
Wolf, & Ramamurthi, 2014). Given the macro-
molecular scope of this book chapter, the focal
point in this chapter will be on large bioactive
proteins like the enzymes, with potential appli-
cability in the pharmaceutical industry.
Enzymes are globular multidomain proteins,
consisting of one or more polypeptide chains,
which act as biological catalysts in living
organisms (Robinson, 2015). Due to their ubiq-
uity in nature, their applications within the
 2.2 Enzymes as bioactive proteins
biomedical field have been actively growing
over the years. While enzymes are essential for
fundamental physiological functions, they also
possess several bioactive therapeutic proper-
ties. Some enzymes can be used as antitumor
and antimicrobial drugs, whereas others can be
used to treat genetic disorders and cardiovas-
cular diseases (Baldo, 2015; Gurung, Ray, Bose,
& Rai, 2013; Sabala, Jonsson, Tarkowski,
& Bochtler, 2012; Thallinger, Prasetyo,
Nyanhongo, & Guebitz, 2013). Moreover,
unlike conventional drugs, enzymes are highly
specific to their substrate, to which they can
bind and act on their targets with great affinity
(Robinson, 2015). The spatial arrangement and
type of amino acids at the active site can pro-
vide a conformation complementary to that of
the substrate, allowing considerable specificity
in their catalytic activity (Ghanem & Raushel,
2012). In certain cases, some enzymes may also
contain another component, known as a cofac-
tor, essential for their catalytic activity
(Andreo-Vidal, Sanchez-Amat, & Campillo-
Brocal, 2018). Other than that, the rest of the
enzyme structure stabilizes the active site, cre-
ating a suitable environment for the interaction
of the site with the corresponding substrate
(Robinson, 2015).
In view of the vast array of enzymes with
bioactive properties that exist, a few examples
of enzymes, whose crystalline structures have
been studied and deposited in the PDB have
been selected for the discussion of their SAR.
These include the L-amino acid oxidases
(LAOs), lysostaphin and metallo-β-lactamase-
like lactonase (MLL). All three enzymes are
active against pathogenic bacteria, except for
LAO which is also active against tumorigenic
cells (Cheleuitte-Nieves et al., 2020; Costa et al.,
2015; López-Jácome et al., 2019; Mukherjee,
Saviola, Burns, & Mackessy, 2015). Each of the
aforementioned enzymes act through catalyz-
ing a distinct type of reaction and using differ-
ent substrates. For these reasons, the LAO,
lysostaphin and MLL are categorized as
I. Background
25
oxidative, proteolytic and quorum-quenching
enzymes respectively (Sabala et al., 2012;
Sikdar & Elias, 2020; Ullah, 2020). The selection
of these specific enzymes highlights the thera-
peutic potential of enzymes, while also under-
pinning their associated structural diversity.
2.2.1 L-amino acid oxidases
The LAOs are one of the most-studied mem-
bers of the flavoenzyme family. They are
widely distributed in nature across diverse
phyla, from fungi and bacteria to plants and
animals (Sabotič et al., 2020; Yang et al., 2011).
In particular, LAOs from snake venoms (SV)
have been extensively investigated to probe
understanding on their ability to induce toxic
physiological effects and to develop snakebite
envenomation treatment (Hossain et al., 2014).
However, it was later demonstrated that SV-
LAOs may additionally possess dose-
dependent antibacterial, antiparasitic, antifun-
gal and antitumor properties (Costa et al.,
2015; Mukherjee et al., 2015; Rey-Suárez et al.,
2018; Soares et al., 2020; Zainal Abidin et al.,
2018). These properties were also observed in
bacterial and fungal LAOs (Andreo-Vidal
et al., 2018; Chen, Lin, Chen, Wang, & Sheu,
2010; Yang et al., 2011). Hence, due to the high
availability of LAOs in nature, their potential
use for therapeutic purposes has been further
spurred.
These enzymes catalyze the oxidative deam-
ination of L-amino acids with a strict stereo-
specificity under aerobic conditions, producing
the corresponding α-ketoacids and ammonia,
while also generating hydrogen peroxide
(H2O2) (Wellner & Meister, 1961). They are
composed of homodimers with a flavin ade-
nine dinucleotide (FAD) as a cofactor and each
protomer (50 70 kDa) contains three con-
served domains: the substrate-binding, FAD-
binding and helical domains (Fig. 2.1)
(Feliciano, Rustiguel, Soares, Sampaio, &
26 2. Structure activity relationship of biological macromolecules

Cristina Nonato, 2017; Pawelek et al., 2000;
Sabotič et al., 2020; Wiezel et al., 2019). Few
exceptions have been reported where LAOs
can exist as monomers or tetramers, with the
latter being only biologically active in their
multimeric form (Andreo-Vidal et al., 2018;
Georgieva, Murakami, Perband, Arni, & Betzel,
2011; Rey-Suárez et al., 2018). A highly con-
served motif β-α-β and a glutamic acid-rich
motif are observed in the N-terminal sequence
of LAOs, important for the FAD binding
(Izidoro et al., 2014; Yu, Zhou, Qiao, & Qiu,
2014). Moreover, 3% 4% of the molecular
mass of most LAOs consist of carbohydrates,
which play a functional role for their antibacte-
rial and antitumor activities (Soares et al., 2020;
Ullah, 2020).
Although the substrate specificity of LAOs
may vary, most LAOs demonstrate a high
affinity for hydrophobic L-amino acids
(Andreo-Vidal et al., 2018; Naumann et al.,
2011; Rey-Suárez et al., 2018; Sabotič et al.,
2020; Soares et al., 2020; Wiezel et al., 2019).
Nevertheless, there are exceptions where
hydrophilic L-amino acids can be the best sub-
strate for some LAOs (Ben et al., 2019;
Nuutinen, Marttinen, Soliymani, Hilden, &
Timonen, 2012). The variation in LAO

FIGURE 2.1 (A) Cartoon representation of the LAO dimer from the Malayan Pit viper Calloselasma rhodostoma.
Opposite charges on the surface of each protomer stabilize the functional dimeric form of the protein. The substrate-
binding, FAD-binding and helical domains for each protomer are colored in green, red and blue respectively. The glycan
moiety is located at the surface of the protein while the cofactor, FAD in buried inside each protomer. (B) Close-up view of
the protomer. Residues Ile374 and Ile430 account for substrate preference of the LAO from Viper a. ammodytes to L-phenyl-
alanine. Residue His223 plays an important role in regulating substrate specificities. Source: (A) From the RCSB PDB (rcsb.
org) of PDB ID 1F8R (Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., et al. (2000). The Protein Data
Bank. Nucleic Acids Research, 28(1), 235 242; Burley, S.K., Bhikadiya, B., Bi, C., Bittrich, S., Chen, L., Crichlow, G.V., et al.
(2020). RCSB Protein Data Bank: powerful new tools for exploring 3D structures of biological macromolecules for basic and applied
research and education in fundamental biology, biomedicine, biotechnology, bioengineering and energy sciences. Nucleic Acids
Research, 49(1), 437 451; Pawelek, P.D., Cheah, J., Coulombe, R., Macheroux, P., Ghisla, S., Vrielink, A. (2000). The structure of L-
amino acid oxidase reveals the substrate trajectory into an enantiomerically conserved active site. The EMBO Journal, 19(16),
4204 4215) (Berman et al., 2000; Burley et al., 2020).

I. Background
 2.2 Enzymes as bioactive proteins
substrate specificities may be explained by the
differences in amino acid composition and
sequence in the loops region, which in turn
influence the surface charge distribution, as
well as the cavity volume and depth at the
active site (Ullah, 2020). For example, the
hydrophobic amino acid residues Ile374 and
Ile430 at the substrate-binding site account for
the preference of the LAO from Vipera ammo-
dytes ammodytes to L-phenylalanine (Georgieva
et al., 2011). Interestingly, the amino acid resi-
due at position 223 in the active site has been
reported to play an important role in regulat-
ing the substrate specificities of LAOs. It was
observed that when alanine or serine occupied
this position, the LAO from Daboia venoms
had higher specificity towards L-arginine as the
substrate-binding cavity was further expanded
and the steric repulsion towards this substrate
was reduced (Chen, Wang, Huang, Huang, &
Tsai, 2012). Hence, position 223 could be fur-
ther exploited for drug design.
The ability of LAOs to inhibit bacterial and
fungal pathogens has been associated with the
exogenous production of H2O2 during the oxi-
dative deamination of L-amino acids, as this
effect was inhibited by the presence of catalase
(Andreo-Vidal et al., 2018; Costa et al., 2015;
Sabotič et al., 2020). It was also suggested that
the most hydrophobic sequences in the amphi-
pathic N-terminus of LAAOs are able to inter-
act with the cell surface of bacteria such as
Staphylococcus aureus and Escherichia coli, subse-
quently destabilizing the cell membrane integ-
rity, which further enhanced the antimicrobial
effect (Abdelkafi-Koubaa et al., 2016; Costa
et al., 2015; Yang et al., 2011). The cell mem-
brane permeabilization may result in an accu-
mulation of H2O2, or the production of other
reactive-oxygen species (ROS) intracellularly
due to an unusual metabolic cytosol environ-
ment. Consequently, cellular damages such as
lipid peroxidation and DNA fragmentation
may occur, leading to bacterial growth inhibi-
tion (Yang et al., 2011). An illustration of the
I. Background
27
antimicrobial activity of LAOs is summarized
in Fig. 2.2.
Apart from their antimicrobial activity,
LAOs can also exert a cytotoxic and antiproli-
ferative effect on different tumorigenic cells
such as leukemia, lung cancer, gastric cancer,
prostate cancer, breast cancer and colon carci-
noma cells (Costa et al., 2015; Li Lee, Chung,
Yee Fung, Kanthimathi, & Hong Tan, 2014;
Naumann et al., 2011; Salama et al., 2018;
Zainal Abidin et al., 2018). It was reported
that the glycan moiety at position 172 on the
protein surface mediates the interaction of
SV-LAOs with the cell surface for a targeted
local release of H2O2. This further enhances
oxidative stress, which consequently leads to
DNA damage and cell apoptosis (Bedoya-
Medina et al., 2019; Bregge-Silva et al., 2012;
Feliciano et al., 2017; Geyer et al., 2001;
Machado et al., 2018; Naumann et al., 2011).
Furthermore, the LAOs can induce proteolytic
enzyme release, which is essential in pro-
grammed cell death via two pathways: via
their interaction with death receptors in the
plasma membrane of tumorigenic cells, such
as the Fas receptor; or through the activation
of the mitochondria-mediated caspase path-
way upon depolarization of the mitochon-
drial membrane due to the accumulation of
ROS (Bedoya-Medina et al., 2019; Mukherjee
et al., 2015; Pišlar, Sabotič, Šlenc, Brzin, &
Kos, 2016; Tan, Ler, Gunaratne, Bay, &
Ponnampalam, 2017; Tavares et al., 2016;
Zhang & Cui, 2007). In the absence of the gly-
can moiety, the catalytic activity of the LAO
is not affected, but the apoptotic activity is
significantly reduced (Ande et al., 2006; Lu
et al., 2018; Ullah, 2020). This demonstrates
that the apoptotic effect is not only brought
about by the production of H2O2, but also
depends on the interaction of the glycan moi-
ety, thus underpinning its importance in the
structure of LAOs.
In summary, based on the general struc-
tural framework of LAOs, it can be observed
28 2. Structure activity relationship of biological macromolecules

FIGURE 2.2 (A) Representation of the catalytic activity of LAO, using L-amino acids as a substrate to release H2O2 as
one of its by-products. (B) Binding of the glycan moiety to the cell surface receptor helps to produce a localized high con-
centration of H2O2, which may accumulate intracellularly. (C) Interaction between the most hydrophobic sequences in the
N-terminus with cell surface may destabilize the cell membrane integrity. (D) Formation of endogenous H2O2 due to
unusual metabolic environment. (E) Accumulation of ROS may lead to DNA fragmentation. (F) ROS production may lead
to lipid peroxidation in the membrane layer.

that the amino acid chain composition at the 2.2.2 Lysostaphin

active site is a major determinant for substrate
specificity of the enzyme. Besides that, hydro-
phobic residues at the N-terminal and the gly-
can moiety are key structural components for
LAOs to exert their bioactive effect on bacte-
rial pathogens and tumorigenic cells. The
important structural features are summarized
in Table 2.1. Nevertheless, although LAOs
seem to hold great antibacterial and antitu-
mor potential, the delivery system of the
LAOs to the site of infection and their thera-
peutic dose still need to be optimized before
they can be used for pharmaceutical
purposes.
Lysostaphin is a 27 kDa monomeric zinc-
containing metalloenzyme of 246 amino acids
produced by Staphylococcus simulans (Schindler
& Schuhardt, 1964). It has been mainly studied
for its ability to inhibit S. aureus, including
methicillin-resistant strains and its biofilms, by
cleaving the crosslinking pentaglycine bridges
in the peptidoglycan layer (Askari, Ahmad,
Abhishek, Waris, & Malakar, 2014; Boksha
et al., 2016; Ceotto-Vigoder et al., 2016;
Cheleuitte-Nieves et al., 2020; Chen et al.,
2014). This enzyme consists of two distinct
domains: the N-terminal peptidase domain

I. Background
 2.2 Enzymes as bioactive proteins 29
TABLE 2.1 Summary of the important structural components of LAO, lysostaphin and MLL associated with their
bioactivities.

L-amino oxidase
Bioactivity Antibacterial and antitumor
Substrate L-amino acids
Cofactor FAD
Domains Substrate-binding domain, FAD-binding domain, Helical domain
Active site Amino acid at position 223 can alter substrate specificity

N-terminal Most hydrophobic sequences interact with bacterial surface to disrupt membrane integrity
Glycan moiety Position 172 mediates interaction with tumor cell surface for localized production of H2O2
Lysostaphin
Bioactivity Antibacterial and antibiofilm
Substrate Pentaglycine cross-bridges
Cofactor Zn21

Domains Catalytic (CAT) domain, cell wall targeting (CWT) domain

Active site His 278, Asp 283 and His 362 residues coordinates the zinc metal ion
Flexible linker Adjusts orientation of CAT and CWT domains for cleaving process
CWT domain Confers target-cell specificity
Binding sites • Located at opposite faces of CWT domain, allowing for lysostaphin clustering
• β1 and β2 in first binding site strands essential for peptidoglycan binding
• Lower affinity of first binding site to pentaglycine for rapid access to CAT domain.

Metallo-β-lactamase-like lactonase

Bioactivity Antivirulence and antibiofilm

Substrate N-acyl homoserine lactones
Cofactor Zn21
Domains HXHXDH motif domain
Active site • Five His and two Asp residues coordinate the dinuclear metal cationic center
• Some AAs may act as hydrogen donors for substrate binding
• Hydrophobic channel accommodates for the amide linkage of AHLs
• Types of Aas influence acyl chain length preference
• Structural variations may influence KM values

responsible for its catalytic activity, and the C- et al., 2014). The catalytic (CAT) domain at the
terminal cell-wall targeting (CWT) domain for active site consists of an antiparallel β-sheet
the binding to the peptidoglycan layer which anchors catalytic residues, grouped
(Fig. 2.3) (Baba & Schneewind, 1996; Sabala around a tightly bound central Zn21 cofactor,

I. Background
Another random document with
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 [12] Islington Wells, or the Threepenny Academy.
[13] Cp. E. Ward, “The Infallible Predictor” (Works, ii. p. 355,
ed. 1709).
[14] An advertisement of 23 May, 1712 (Percival’s Sadler’s
Wells announces the performances from six to ten in the morning
and from four till eight in the evening of two wonderful posture-
makers, a man and a child of nine, to take place in the dancing-
room of New Tunbridge Wells.
[15] Extract from family correspondence communicated by C.
L. S. to Notes and Queries, 8th ser. vi. 1894, p. 69.
[16] In 1760 the breakfasting was ninepence, the afternoon tea
sixpence, and the coffee eightpence. No stronger beverages were
sold.
[17] A serious attempt seems to have been made to keep this
rule. The London Daily Advertiser for 25 June, 1752, records that
a beautiful though notorious woman, who had appeared at the
dancing at New Tunbridge on June 24, was, on being recognised
by the company, turned out by a constable.
[18] Dr. Russel, who analysed the water about 1733, says that
it had a taste of iron and (unless mixed with common water) was
apt to make the drinker giddy or sleepy. This was the experience
of Lady Mary Wortley Montagu, who, however, expatiates on the
benefit she had derived from the Spa.
[19] This was between the main part of the Spa gardens and
St. John’s Street Road; cp. Wallis’s Plan, 1808.
[20] A band had played in the morning under Holland’s
management (advertisement in the Public Advertiser, 5 May,
1775).
[21] Malcolm, Lond. rediv. iii. 230, 231.
[22] The orchestra connected with it was pulled down in 1827;
Cromwell’s Clerkenwell, p. 357.
[23] No. 6, Eliza Place, stood on the site of the old entrance
(Pinks).
[24] Mr. Philip Norman, writing in Notes and Queries, 8th ser.
vi. 1894, p. 457, says:—“I have seen (in the cellar of No. 6, Spa
Cottages, behind the house at the corner of Lloyd’s Row) grotto
work with stone pilasters and on each side steps descending.
Here, I believe, was the chalybeate spring. For many years it has
ceased to flow.”
[25] Daily Telegraph, 1 August, 1895.
[26] A newspaper paragraph of April 1752, mentions the little
summer house at the Ducking Pond House in Spa Fields, as
being lately stripped of its chairs and tables by some pitiful
rogues.
[27] In The Macaroni and Theatrical Magazine for January
1773 (p. 162) is the notice:—
“Pantheons: The Nobility’s, Oxford Road; the Mobility’s,
Spawfields.”
[28] The organ appears, about 1772, to have been silenced on
Sundays, at least for a time. A correspondent in The Gazetteer
and New Daily Advertiser for 20 June, 1772, refers to the
Middlesex Justices who will not suffer the organs to be played at
the Little Pantheon, White Conduit House, Bagnigge Wells, &c.
[29] May Day, or the Origin of Garlands, a poem published in
1720. The Field Spy, published in 1714 (Rogers, Views of
Pleasure Gardens of London, p. 46), speaks of the spring and
garden as if a good deal frequented in 1714.
[30] A rare bronze ticket of oblong form, incised with the words,
“London Spaw No. 19,” is in the possession of Mr. W. T. Ready,
the London coin dealer. It may belong to about the middle of the
last century.
[31] Rosoman Street was called after Mr. Rosoman, who about
1756 built the west side, which was then called Rosoman Row.
Rosoman, who acted at the New Wells in 1744, was the well-
known proprietor of Sadler’s Wells. Pinks (Clerkenwell) states that
the houses numbered (in his time) 5 to 8 occupied the site of the
Wells.
[32] The New Wells seem to have been already established in
1737. The earliest advertisement quoted in Pinks is of 1738, but
there are earlier advertisements (W. Coll.), May to August 1737,
in one of which reference is made to the alterations in the theatre
that season.
[33] Daily Post, 3 July, 1742 (quoted in Gent. Mag. 1813, pt. ii.
p. 561).
[34] Doran’s London in Jacobite Times, ii. pp. 148, 149.
 [35] The English Grotto has escaped the minute research of
Mr. Pinks, and his continuator Mr. Woods (cp. however, Daniel,
Merrie England, i. chap. ii. p. 33). It is practically known only from
the following views:—
(1) A view of the English Grotto, near the New River
Head. Chatelain del. et sculp. 1760. Crace, Cat. p. 591,
No. 60 (cp. engraving (circ. 1760), without artist’s name,
in W. Coll.).
(2) The Grotto, near the New River Head, 1760. A
drawing in Indian ink. Crace, Cat. p. 590, No. 59.
(3) A water-colour copy of No. 1 by R. B.
Schnebellie. Crace, Cat. p. 591, No. 61.
[36] The continuator of Pinks (p. 740) quotes advertisements of
1769, without, however, specifying the newspapers referred to. J.
T. Smith, Book for a Rainy Day, p. 70, refers to the Grotto Garden
as being kept by Jackson in 1779. Pinks (p. 169) mentions the
fountain and Grotto in 1780, and describes the site.
[37] Rockhoutt = Rockholt House in Essex.
[38] The legs referred to are those of Sir Thomas Robinson,
the principal proprietor of Ranelagh, nicknamed Long Sir Thomas.
[39] The New Wells, Clerkenwell.
[40] Cuper’s Gardens, Lambeth.
[41] Newspaper advertisement in “Public Gardens” collection in
Guildhall Library, London.
[42] Advertisement in Daily Advertiser, 8 July, 1745.
[43] Sadler originally advertised the place as “Sadler’s New
Tunbridge Wells,” but it soon became known simply as Sadler’s
Wells. On the confusion with the neighbouring New Tunbridge
Wells (Islington Spa), see Islington Spa, supra, note 3.
[44] About 1800 the forgotten well was accidentally re-
discovered between the stage door and the New River.
[45] A poem by William Garbott, entitled the New River,
published probably about 1725.
[46] A new song on Sadler’s Wells, set by Mr. Brett, 1740.
[47] The Sadler’s Wells anglers are mentioned in the Field Spy,
a poem of 1714. The New River remained open until 1861–62
when it was covered in.
[48] A newspaper cutting in “Public Gardens” collection in
Guildhall Library, records the death on 2 February, 1786, of Mrs.
Bennet, of Merlin’s Cave, Spa Fields, who was the successor of
her uncle, Mr. Hood.
[49] A view of the Merlin’s Cave at Richmond forms the
frontispiece of Gent. Mag. 1735; on the cave, see Walford’s
Greater London, ii. 345, ff
[50] A square stone bearing the inscription given below was,
about 1760, over an old gateway in the wall to the north of the
Long Room, and was still there in 1843. In 1850 it was to be seen
in Coppice Row, now Farringdon Road.
ST
THIS IS BAGNIGGE
HOUSE NEARE
THE PINDER A
WAKEFEILDE
1680.
The Pinder a Wakefielde (the modern representative of which
stands near the old site in Gray’s Inn Road) was a tavern; and
some writers have inferred from the above inscription that
Bagnigge Wells itself was a place of entertainment as early as
1680.
[51] Over one of the chimney-pieces of the room was the garter
of the order of St. George, in relief, and over another the bust of a
woman in Roman dress, popularly supposed to represent Nell
Gwynne. This bust was let into a circular cavity of the wall,
bordered with festoons of fruit and flowers moulded in delft earth
and coloured after nature. Owing to the number of visitors
promenading in the Long Room to the hindrance of the waiters,
the room was, before 1797, divided into two, though we are told
that the “former elegance” remained.
[52] The organ and its organist (under Davis), Charley Griffith,
are shown in an engraving “The Bagnigge Organfist” (undated).
“Published for the benefit of decayed musicians.”
[53] Picture of London, 1802.
[54] “Bagnigge Wells,” a song in the London Magazine, June,
1759.
 [55] Colman’s prologue to Garrick’s Bon Ton, 1775.
[56] This is made sufficiently clear in the Sunday Ramble
(1774, &c.); in the poem cited in the next note, and in Trusler’s
London Adviser (1786).
[57] Bagnigge Wells, an anonymous poem (1779).
[58] The life of John Rann, otherwise Sixteen Strings Jack,
reprinted London, 1884; C. Whibley in The New Review, 1896, p.
222; cp. also the print “The Road to Ruin.”
[59] Sale Catalogue, 1813. (Copy in Brit. Mus.)
[60] A few years before 1891, these figures were in the
possession of Dr. Lonsdale of Carlisle (Wheatley’s London P. and
P.).
[61] The temple (behind the Long Room) and the grotto to the
north of it, were, as formerly, in the garden east of the Fleet. The
western garden, previous to its curtailment, contained the rustic
cottage nearly opposite the grotto, and the pond with its swan and
Cupid fountain about the middle of the garden.
[62] For New Year’s day 1751, new fireworks in the Chinese
manner were announced to take place at the Sir John Oldcastle
(Pinks, p. 738). This was a special subscription entertainment.
The regular open-air amusements appear to have come to an end
in 1746.
[63] The Well at Battle Bridge (i.e. St. Chad’s) is mentioned
with four other London Wells in the Macaroni and Theatrical
Magazine for January 1773, p. 162. A Mr. Salter was part
proprietor of the Well for many years previous to 1798. His mind
became deranged and on 17 July, 1798, he was found drowned in
a pond in the garden of St. Chad’s (The Courier for 18 July,
1798).
[64] Coull’s St. Pancras, p. 22.
[65] In the minutes of a Vestry Meeting in St. Giles’s parish,
held in 1676, it is recorded that a meeting is appointed with the
parishioners in St. Andrew’s, Holborn, about the Bowling Green in
Gray’s Inn Fields and the houses near thereabouts built (F.
Miller’s St. Pancras, p. 77).
[66] Malcolm’s Manners and Customs of London (1811), p.
209.
 [67] Barras’s advertisement is quoted in Palmer’s St. Pancras,
p. 310.
[68] It was generally known as the Bowling Green House, but
the sign of the inn appears to have been the Three Tuns, for in a
plan of the new road from Paddington to Islington (London Mag.
1756), the place is marked as the Three Tuns Ale House and the
Three Tuns Bowling Green.
[69] Malcolm in Gent. Mag. 1813, pt. 2, pp. 427–429. The
Bowling Green House is marked in Horwood’s Plan C, 1799; in a
map of 1806 in Lambert’s London, vol. iv., and in Wallis’s plan of
1808.
[70] Walford, v. 304, cites a newspaper advertisement of
September 1718, announcing that “there is a strange and
wonderful fruit growing at the Adam and Eve at Tottenham Court,
called a Calabath, which is five feet and a half round, where any
person may see the same gratis.”
[71] Cunningham’s Handbook of London (1850), “Tottenham
Court Road”; see also Paxton’s History of St. Giles’ Hospital and
Parish (cited in F. Miller’s St. Pancras, p. 161), where similar fines
for drinking at Tottenham Court are recorded for the year 1644.
[72] His first ascent was on 15 September, 1784. This was the
first ascent in England, but it may be noted that Mr. J. Tytler had
made an ascent from Edinburgh on 27 August, 1784.
[73] The Morning Herald and Daily Advertiser, Saturday, 14
May, 1785.
[74] See Horwood’s Plan, 1793.
[75] See Wallis’s Plan, 1808.
[76] Thus the grounds must at that time have covered the
space now occupied by Eden Street and Seaton (formerly Henry)
Street.
[77] There may be some exaggeration in this description
(based on Wilkinson), for in the Picture of London, 1802, p. 370,
the Adam and Eve is enumerated among the tea-gardens
frequented by the middle classes, and is described as somewhat
similar to the Jew’s Harp, with a small organ in the room upstairs
where tea, wine and punch are served.
[78] Walford, v. 305.
[79] Stow’s Survey, p. 7 (ed. Thoms).
 [80] At a depth of four feet was a bottom of “lettice” work under
which the water was five feet deep.
[81] Watts’s building operations do not appear to have been
completed till about 1811 or later (cp. Hughson’s London, iv.
(1811), p. 414).
[82] Peerless Pool is mentioned in The Picture of London, 1829
(p. 370), as one of the principal public baths of London.
Cunningham, Handbook of London, 1850, speaks of it as a then
existing public bath. Mr. Hyde Clark writing in Notes and Queries
(7th Series, viii. 214, 215) for 14 September, 1889, says that “it
continued to be used as a bath until comparatively late years.” I
am informed that after the death of Joseph Watts, the Bath was
carried on by his widow, Mrs. Watts, and by the sons, Thomas
Watts of the British Museum and his brother. It seems to have
been built over at some time between 1850 and 1860.
[83] The grounds originally extended on the north-east to a
tavern called The Fountain, which was frequented by tea-parties:
—

And there they sit so pleasant and cool,

And see in and out the folks walk about,
And gentlemen angling in Peerless Pool.

(Lines in Hone, loc. cit.). There is now a public house called

The Old Fountain at the east end of Baldwin Street. The
Shepherd and Shepherdess (q.v.) was close by on the other side
of the City Road.
[84] Cp. Lewis’s Islington, p. 31, note 6, referring to August
1758.
[85] For the connexion of the Salvation Army with the Eagle,
and for some details as to the history of the Eagle tavern and
gardens see The Times for 1882 (Palmer’s Index, under
“Salvation Army,” June to September). On the Eagle see also
Dickens, Sketches by Boz (Miss Evans and the Eagle);
Hollingshead’s My Lifetime, i. p. 25, ff.; Ritchie’s Night-side of
London (1858); Stuart and Park, The Variety Stage, p. 35, ff. &c.;
Era Almanack, 1869, p. 80; H. Barton Baker’s The London Stage,
ii. p. 254, ff.; and a view of the garden in Rogers’s Views of
Pleasure Gardens of London, p. 57.
 [86] The Post Man, Oct. 3 to 6, 1702, has the advertisement
“At Milend the garden and house called the Jews Spring Garden
is to be let. Enquire at Capt. Bendal’s at Milend” (Notes and
Queries, 1st ser. ii. 463). Mr. Alexander Andrews (ib. 2nd ser. viii.
422) has shown that this Jews’ Spring Garden is in all probability
to be identified with the Spring Garden marked in a map of
Stepney parish of 1702.
[87] Rayner, Master of the Spring Garden at Stepney, died April
3, 1743, aged 70 (London Daily Post for 6 April, 1743).
[88] Low Life (1764), “Stepney Spring Gardens.”
[89] Dodsley’s London (1761), s.v. “Stepney.” There are
modern streets known as Garden Street and Spring Garden
Place, but these are some distance south of the Mile End Road,
not far from St. Dunstan’s, Stepney.
[90] See Crace, Cat., p. 616, No. 80.
[91] “The back entrance was from the fields, beyond which,
north, was a narrow winding passage, with garden palings on
each side, leading into High Street” (Smith’s Book for a Rainy
Day, p. 39).
[92] Pulled down in 1791. Devonshire Mews was built on the
site.
[93] These lines, often erroneously attributed to Lady Mary
Wortley Montagu, occur in Pope’s The Basset-table, an Eclogue.
The allusion in the second line is to Sheffield, Duke of
Buckingham.
[94] Gough issued, 1738–9, silver tickets at 12s. each,
admitting two persons for the season. In 1740 the silver season-
ticket, admitting two, cost £1 1s. There are extant silver (or rather
base silver) season tickets of 1766 (Wilkinson, Londina, vol. ii.,
last plate, No. 19) and of 1767 (Brit. Mus.). These later tickets,
admitting two, cost £1 11s. 6d., or two guineas. There are copper
tickets of 1770 (specimen in Brit. Mus.). In 1774 the ticket for two
cost two guineas.
[95] The use of the old spelling which occurs in all the
advertisements and contemporary notices must be conceded.
[96] J. T. Smith and several modern writers state that Trusler
was proprietor in 1751. It would appear, however, from the
newspapers that in 1754 John Sherratt was proprietor, and in May
1755 Mr. Beard was stated to have “lately taken the Gardens.”
Trusler was undoubtedly manager from 1756–1763. He died
before October 1766.
[97] Cp. Vocal Melody, Book iii. A favourite collection of songs
and dialogues sung by Master Arne and Miss Faulkner at
Marybone Gardens, set by Mr. Arne. Published 15 August, 1751,
by J. Walsh, Catherine Street, Strand.
[98] The name is variously spelt; usually Falkner.
[99] See Trusler’s Memoirs, p. 63, ff.; cp. Dict. Nat. Biog., art.
“Dunk, George Montagu, second Earl of Halifax,” 1716–1771.
[100] The Servant Mistress, a burletta translated from the
Italian. Price 6d., printed at Marybone Gardens.
[101] Hone’s Year Book, pp. 500–503.
[102] Trusler’s Memoirs, p. 57.
[103] Two men were executed 15 June, 1763, at Tyburn for
robbing, in Marybone Fields, the waiters belonging to Marybone
Gardens.
[104] Indenture between Robert Long and Thomas Lowe,
dated 30 August, 1763. The lease was for fourteen years. Trusler
ceased to reside at the Gardens in 1764 when he went to Boyle
Street, Saville Row, and Miss Trusler carried on business as a
confectioner.
[105] The vocalists 1763–1767, besides Lowe, were—1763,
Mrs. Vincent, Mrs. Lampe, Miss Catley, Miss Hyat, Miss Smith,
Miss Plenius (1763?), and Mr. Squibb (Sig. Storace and Miss
Catley had benefits); 1764, Mrs. Vincent, Mrs. Lampe, Miss
Moyse, Miss Hyat, Mr. Squibb; 1765, Mrs. Vincent, Mrs. Collett,
Miss Davis, Mrs. Taylor, Mr. Legg; 1766, Mr. Taylor, Mr. Raworth,
Mrs. Vincent, Miss Davis; 1767, Mrs. Gibbons.
[106] The vocalists in 1768 were Reynoldson, Taylor, Phillips,
Miss Davis, Miss Froud.
[107] Performers in 1769: Pinto, leader; Hook; Park, hautboy.
Vocalists, Mrs. Forbes, Miss Brent, Mr. Herryman, Mr.
Reynoldson.
[108] Performers, 1770: Barthelemon (violin); Hook; Reinhold,
Charles Bannister; Mrs. Thompson; Mrs. Barthelemon; Mrs.
Dorman. It is well known that Thomas Chatterton the poet wrote a
burletta called The Revenge, which he sold to the management of
Marybone Gardens for five guineas. It was not published till 1795,
when it was issued as The Revenge, a burletta acted at
Marybone Gardens, MDCCLXX. In the Marybone Gardens’
advertisements of 1770 (and of later dates) no burletta bearing
the name of The Revenge appears, and the writer of the article
“Chatterton” in Dict. Nat. Biog. thinks that the burletta must have
been performed at some time subsequent to 1770, the year of
Chatterton’s death. In The Revenge as published, the dramatis
personæ are Jupiter, Mr. Reinhold; Bacchus, Mr. Bannister;
Cupid, Master Cheney; Juno, Mrs. Thompson. Reinhold,
Bannister, and Mrs. Thompson sang at the Gardens 1770–1773,
and Cheney in 1770. I may add that a burletta called The
Madman, performed at the Gardens in 1770, has a plot quite
distinct from that of The Revenge.
[109] Performers, 1771: Hook; solo violin, Mons. Reeves;
Charles Bannister; Mrs. Thompson; Miss Esser; Miss Harper
(afterwards Mrs. John Bannister); Miss Thomas; and Miss Catley
who sang “The Soldier tired of War’s Alarms”; “Sweet Echo,” from
Comus (the echo “sung by a young gentleman”), &c.
[110] According to J. T. Smith (Rainy Day, p. 52, n.), Torré was
a print-seller in partnership with Mr. Thane, and lived in Market
Lane, Haymarket. Other fireworkers at the Gardens at this period
were Clitherow (1772); Clanfield (1772 and 1773); Caillot of
Ranelagh (1773, 1775, 1776).
[111] Performers, 1772: Hook, organ; Charles Bannister,
Culver, Reinhold, Mrs. Calvert, Mrs. Forbes, Mrs. Foster, Mrs.
Cartwright and Mrs. Thompson.
[112] On his own benefit night in July 1772, Torré gave a
representation of Hercules delivering Theseus from Hell, in
addition to the Forge of Vulcan.
[113] Performers, 1773: Charles Bannister; Reinhold; Phillips;
Barthelemon (leader); Miss Wilde; Mrs. Thompson; Mrs.
Barthelemon. “Mr. Dibdin, of Drury Lane Theatre,” was
announced to sing in Barthelemon’s “La Zingara, or the Gipsy” on
Barthelemon’s benefit night.
[114] Also on 13 June, 1774.
[115] Performers, 1774: Fisher (violin), Dubellamy, Reinhold;
Mons. Rodell, “musician to the King of Portugal,” German flute;
Miss Wewitzer, Miss Trelawny, Miss Wilde.
 [116] A large printed bill referring to this entertainment is in the
possession of Mr. H. A. Rogers, and is reproduced in his Views of
Pleasure Gardens of London, p. 30.
[117] Nollekens, i. 33, chap. ii.
[118] At a bazaar held in the Portman Rooms, Baker Street, in
1887 (Nov. 22–26), for the benefit of the charities of Marylebone
Church, an ingenious reproduction was attempted, under the
direction of Mr. Thomas Harris, the architect, of the latticed
alcoves, lamp-hung trees, &c., of the old Marybone Gardens (see
A Booke of ye olde Marybone Gardens, 1887 (sold at the bazaar);
Daily Telegraph for 23 November, 1887).
[119] An account of the robbery and murder in 1808 of Mr.
William Joachim in the Marylebone Fields mentions that he was
on his way home to Lisson Grove, after a visit to the Jew’s Harp
Tavern to see the skittle-playing (F. Miller’s St. Pancras, p. 238).
[120] Wheatley, London Past and Present, s.v. “Yorkshire
Stingo,” states on the authority of Cooke’s Old London Bridge, p.
7, that a bridge designed by the celebrated Thomas Paine, being
the second cast-iron bridge ever constructed, was brought to
London in 1790 and set up in the bowling-green of the Yorkshire
Stingo; it was afterwards taken back to Rotherham (where it had
been made in 1789) and broken up in 1791.
[121] The Picture of London, 1802, p. 370, mentions the
Yorkshire Stingo as a house many years celebrated for rustic
sports on May Day.
[122] Newspaper cuttings in W. Coll.; cp. Hollingshead’s My
Lifetime, i. 24, and see also Stuart and Park, The Variety Stage,
p. 38, who mention Cave and Glindon as the comic vocalists. The
saloon, which was in the rear of the tavern, had a small but
capable orchestra directed by Love, afterwards leader at the
Princess’s Theatre under Charles Kean. Miss Tunstall of Vauxhall
was at one time a singer there.
[123] Pulled down about 1895.
[124] Woodward’s Eccentric Excursions, p. 18.
[125] Before 1702.
[126] The Country Journal, or the Craftsman, 7 March, 1729–
30. If an allusion in a pamphlet of 1735—A seasonable
examination of the pleas and pretensions of ... Playhouses
erected in defiance of Royal Licence (London, printed for T.
Cooper, 1735)—may be relied on, Pancras Wells had about that
time some kind of (unlicensed) theatrical or “variety”
entertainments resembling those of Sadler’s Wells.
[127] According to Roffe (St. Pancras), Pancras Wells
occupied the south side of Church Hill from its base to its summit.
Palmer in his St. Pancras, published in 1870, says the Well “is
now enclosed in the garden of a private house, neglected and
passed out of mind.”
[128] It is shown in the bird’s-eye view of Pancras Wells of
1730. In April 1731, James Dalton, a notorious footpad, robbed a
linenpedlar at night near the Adam and Eve after drinking with
him at the tavern (Pinks’s Clerkenwell, p. 549).
[129] The Connoisseur, 1754, No. 26.
[130] Five of these pier-glasses were stolen from the long room
in 1778 (London Evening Post, 11–14 July, 1778).
[131] Advertisement of 1786 quoted in Clinch’s Marylebone
and St. Pancras, p. 157.
[132] There are advertisements of the Adam and Eve issued
(at the end of the eighteenth and beginning of the nineteenth
century?) by G. Swinnerton, Junr. and Co., and by George
Lambert (quoted in Walford, vol. v. p. 338). The Picture of
London, 1805, mentions the Adam and Eve Tea-gardens,
bowling-green, &c., but the conversion of the gardens into the
cemetery (authorised by Act of Parliament in 1803) appears to
have been already carried out in 1804.
[133] There is a mention of the inn in 1725: the Assembly
Rooms were certainly in existence in 1750, and perhaps at an
earlier date. The original sign of the inn appears to have been the
Black Bull; see Notes and Queries, 1st ser. viii. p. 293; W. Elliot’s
Some Account of Kentish Town (1821), p. 65.
[134] The new or altered building contained the circular
structure shown in so many views of the place.
[135] The White Conduit meadow long continued in use as a
cricket ground. About 1784 and subsequently a club composed of
gentlemen and men of rank played its matches there. Among the
players were the Duke of Dorset, Lord Winchilsea, Lord Talbot,
Col. Tarleton, and Thomas Lord, who afterwards established the
Marylebone Cricket Club.
 [136] A poem by W. W[oty] printed in the London Chronicle,
1760, vol. vii. p. 531.
[137] “White Conduit Loaves” was a London cry till about 1825.
[138] Forster’s Life of Goldsmith; cp. Goldsmith’s Citizen of the
World, Letter 122.
[139] “An Awkward Position,” a painting by A. Solomon, depicts
the situation. This was exhibited in the Royal Academy, and
reproduced in the Illustrated London News, 14 June, 1851.
[140] Ashton, The Fleet, p. 66.
[141] Bartholomew sold his interest in White Conduit House 25
March, 1795.
[142] About 1772 these performances were prohibited on
Sundays.
[143] See a bill in the London Sections Collection, Guildhall
Library, and cp. Rogers’s Views of Pleasure Gardens of London,
p. 55; also G. Cruikshank’s Ivan Ivanitz Chabert, a print published
13 March, 1818. Hone’s Every Day Book, ii. p. 771, ff.
[144] Born 1769, died 1838.
[145] Till May of 1829 the old building was still standing.
[146] Hone’s Every Day Book, ii. p. 1204.
[147] Cp. the White Conduit concert described in the Sketches
by Boz (“The Mistaken Milliner,” cap. viii.).
[148] The Variety Stage, by Stuart and Park, p. 8; 103.
[149] The place appears to be referred to as early as 1633 as
“the bowling place in Islington Fields” (Pinks, p. 710).
[150] Mrs. Dobney died at about the age of ninety on 15 March,
1760.
[151] Pinks states that Price had been starring at the Three
Hats, Islington, prior to his performance at Dobney’s in 1767 (cp.
Memoirs of J. de Castro (1824), p. 29, who says that Price,
Thomas Johnson, and old Sampson exhibited at the Three Hats).
This may have been the case, though from 1758 to the spring of
1767, Thomas Johnson was certainly the chief equestrian
performer at the “Three Hats.”
[152] London Evening Post, August 1776. The Pantheon is the
tea-house in Exmouth Street.
 [153] Tomlins in his Perambulation of Islington, published in
1858, but written in part about 1849, describes Prospect House
as still existing behind Winchester Place, though the bowling
green (he says) had been already covered by Winchester Place.
[154] Busby’s Folly is first mentioned in 1664 as a meeting-
place of the Society of Bull Feathers Hall, a fraternity of Odd
Fellows. It is supposed to have derived its name from Christopher
Busby, landlord of the White Lion Inn, Islington, in 1668.
[155] Prologue written and spoken by Mr. Gibson before the
Orphan at the New Theatre in the Haymarket on 31 May, 1762
(Owen’s Weekly Chronicle or Universal Journal, June 5 to 12,
1762). The “wonder of a Chelsea field” mentioned in this prologue
is evidently Coan, the dwarf (called “the jovial pigmy”), who
attracted visitors to the Dwarf’s Tavern in Chelsea Fields (see
infra, Star and Garter, Chelsea).
[156] According to Nelson and Lewis, the house facing to the
south at the northern termination of Colebrooke Row, was
occupied about 1772 by the Rev. John Rule, who there kept a
school, of some repute, for gentlemen’s sons. The Castle Inn was
the adjoining house and a house next to the Castle was supposed
by a doubtful tradition (cp. J. Knight, art. “Cibber” in Dict. Nat.
Biog.) to be that in which Colley Cibber died 12 December, 1757
(see Nelson and Lewis). The old house with a red-tiled roof, still
existing, though divided into the dwelling houses Nos. 56 and 57
Colebrooke Row, was apparently the Castle Inn. The southern
end of Colebrooke Row was built in the present century. The Row
also now extends a little farther to the north than when Nelson
wrote, so that Rule’s house is not now at the extreme northern
end of the Row.
[157] Sampson’s Riding School at Islington is mentioned in the
Macaroni and Theatrical Magazine for January 1773, p. 162,
together with Astley’s and Hughes’s.
[158] They were probably in existence before this date, but are
not marked in the survey of Islington of 1735. An advertisement in
The Morning Herald of 22 April, 1786, announces the sale of the
ground-rents of an Islington copyhold estate. This estate, situated
“in the Lower Street, opposite Cross Street, Islington, and
extending down to Frog Lane,” comprised a brick mansion and
garden, four dwelling-houses and gardens, and the Barley Mow
Tea House and Gardens. A plan of the estate was to be seen at
Mr. Spurrier’s, the auctioneer’s, Copthall Court, Throgmorton
Street. The estate was therefore between the present Essex
Road, where it is touched by Cross Street, and Popham Road.
[159] See the survey of roads in Islington parish in 1735
(Nelson’s Islington, p. 20).
[160] Hone, Every Day Book, i. p. 860. Tomlins (Islington, 204,
205) discovered that in 1753 it was occupied by a currier, and
supposes, therefore, that it was not a place of entertainment till
after that date. The meeting of the Highbury Society there before
1740 seems however to bear out Hone’s assertion that
Copenhagen House was already an inn in the first half of the
eighteenth century.
[161] Map in Gibson’s edition of Camden’s Britannia, 1695.
[162] Hone, however, shows (op. cit. 860) that there is some
reason for supposing that Copenhagen House was not in
existence until after 1624.
[163] On the Highbury Society, see note infra under Highbury
Barn.
[164] The graphic account in Hone (op. cit. 862) is worth
reading, though too long for quotation here.
[165] Hazlitt’s memoir is published in the Examiner for
February 17, 1819; most of it is reprinted in Hone’s Every Day
Book, i. 865, ff.
[166] Picture of London, 1823 and 1829; Hone’s Every Day
Book, i. 859, 870.
[167] The hay-harvest is referred to in Nelson’s Islington, 1811,
74. A view of 1809, published by Cundee in the Juvenile Tourist,
1810, shows cockney visitors playing in the hay.
[168] Plan in Lewis’s Islington.
[169] J. Hollingshead’s My Lifetime, i. 13. The cricket ground
was between Copenhagen House and Maiden Lane.
[170] Tomlins, Perambulation of Islington, p. 205.
[171] F. Miller, St. Pancras, 269.
[172] Highbury Barn, i.e., the grange or farm of Highbury
Manor, is mentioned by that name at an early period, and there
are extant various leases of it of the fifteenth century, granted by
the Prior and Convent of St. John of Jerusalem (e.g. “our certain
grange, situate upon the site of our manor of Highbury called
Highbury Barn”—see Tomlins’s Perambulation of Islington). The
name Highbury Barn is, therefore, much older than the date of the
incorporation of the large barn of Highbury Farm with the
Highbury Tavern premises.
[173] The site of the Prior’s house was occupied by a private
residence called Highbury House built in 1781 and immediately
opposite the Highbury Barn Tavern.
[174] The Highbury Society, formed by Protestant Dissenters to
commemorate the abandonment of the Schism Bill at the end of
the reign of Anne, met at first at Copenhagen House, but about
1740 assembled at Highbury Barn. The members beguiled their
pilgrimage from Moorfields to Highbury by bowling a ball of ivory
at objects in their path. This society was dissolved about 1833.
[175] The younger Willoughby was certainly proprietor in 1792
and later, and Lewis says he succeeded his father on the death of
the latter in December 1785. In May 1789 Highbury House
(Nichols, Canonbury, p. 31, note) opposite the Tavern was sold by
auction, as were also Highbury Tea House with gardens and
bowling-green and two good messuages adjoining, together with
many fields in the neighbourhood. This sale does not, however,
necessarily imply any change in the management of Highbury
Barn, which may at that time have been only rented by
Willoughby from the owner of Highbury House and the adjoining
property.
[176] A few years previous to 1811 Willoughby cultivated at
one end of the gardens a small plantation of hops, and afterwards
erected a brewery on the premises. Highbury Barn was
sometimes called “Willoughby’s Tea Gardens” (Picture of London,
1802).
[177] Lysons, Nelson and Lewis all identify the moated house
called in the Survey of 1611 “The Devil’s House” or the “Lower
House” with the old Tallington or Tollington Manor House. In the
survey of the roads of Islington (Nelson’s Islington, p. 20),
however, both Tallington House and Devil’s House are separately
marked, the two being divided by Heame Lane, a lane running at
right angles to Tallington (Devil’s) Lane. This Tallington House
must therefore have been an eighteenth-century residence and
not the old Manor House.
[178] Nelson (Islington), writing about 1811, says that about
thirty or forty years before his time (1776?) the landlord’s name
was Fawcett.
[179] This seems to be implied by Nelson (Islington, 1811),
who says that in his time the old “house had been fitted up in the
modern taste.”
[180] Lewis’s Islington, 1841, mentions the house as still
existing, and it is described as still standing in Tomlins’s
Perambulation of Islington, a work published in 1858, but in part
written nine years before the date of publication.
[181] Tea-drinking on Sunday at Little Hornsey is mentioned in
the Connoisseur, No. 68, May 15, 1755, and Hornsey Wood is
referred to in The Idler, No. 15, July 1758, in a way which implies
that its reputation as a place of Sunday recreation was already
well established. It appears from a passage in Low Life, referred
to in the next note, that in or before 1764 the sign of the tavern
was The Horns. The place was, however, usually known as
Hornsey Wood House, and in its latest days as Hornsey Wood
Tavern.
[182] Low Life (1764), p. 46.
[183] Mr. Rose, the “citizen at Vauxhall,” described in the
Connoisseur, May 1755, No. 68, used to grumble when his wife
and daughters went “to Little Hornsey to drink tea.”
[184] Newspaper cutting, 1753 (W. Coll.).
[185] See Boyne’s Trade Tokens, ed. Williamson, ii. p. 818.
This token is undated. The only dated token of Hampstead is one
of 1670.
[186] The “Mirmillo” of Garth’s Dispensary.
[187] The modern public-house in Well Walk called the Wells
Tavern, though at one period, (before 1840) bearing the sign of
the Green Man, is probably on the site of the original tavern.
[188] Sion Chapel (the exact site of which is unknown) is of
course distinct from the Episcopal Chapel into which the Great
Room was converted in 1733.
[189] Baker’s comedy, Hampstead Heath, London, 1706.
[190] The Country Journal, or the Craftsman for 16 October,
1736, has the notice:—“On Sunday between seven and eight in
the evening one Mr. Thomas Lane, a farrier of Hampstead, going
home from the Spaniards upon the Heath near the house called
Mother Huff’s,” was attacked and robbed and stripped naked by
three men who jumped out of the bushes.
[191] Lysons’s Magna Britannia, vol. iii. 1724, p. 44.
[192] This lady had made an earlier appearance at Cuper’s
Gardens; see Welsted’s Epistle on False Fame.
[193] The spring at this time was adjacent to the Great Room,
and was in this position, i.e. on the opposite side to the existing
fountain, at any rate as late as 1806.
[194] In Bickham’s Musical Entertainer (1733, &c.).
[195] Evelina (1778), letter li.
[196] The house, No. 17 in Well Walk, which is just behind the
existing fountain, has a shallow well supposed to contain the
source of the original spring.
[197] MS. History of Middlesex, 1752, quoted by Park.
[198] A Modern Sabbath, 1797, p. 53; see also Woodward’s
Eccentric Excursions, 13.
[199] Dickens, Pickwick Papers, cap. xlvi.
[200] Cp. The Idler, No. 15, July 1758.
[201] Lysons, Environs, ii. 527.
[202] Evelyn (Diary, 2 June, 1676) describes the gardens as
very large and woody, but ill kept.
[203] E.g. “Galloway Races” in 1725 and 1729.
[204] Ambulator, 1774; Dodsley’s London, 1761.
[205] From the manuscript history of Middlesex quoted by Park
(Hampstead), the spring would appear to have been discovered
about 1742; the date on the reservoir containing the water was,
however, 1714, and Walford (v. 245) states that the spring was
known before 1600. But there is no evidence that Kilburn Wells
was a place of entertainment earlier than about 1742, though the
Bell tavern dated from about 1600.
[206] Richard Owen Cambridge, Dialogue between a master
and his servant (1752). “Kupers” = Cuper’s Gardens, Lambeth.
[207] Picture of London, 1802 and 1829.
[208] Gibson, View of the Gardens near London, Dec. 1691.
 [209] Lord Ranelagh’s house remained standing till 1805, and
was used in connexion with the Ranelagh entertainments.
[210] Robinson lived at Prospect Place adjoining the gardens.
He died on 3 March, 1777.
[211] Cp. Walpole’s letter to Mann of 26 May, 1742: “The
building and disposition of the gardens cost sixteen thousand
pounds.”
[212] Walpole to Mann, 26 May, 1742.
[213] Walpole to Conway, 29 June, 1744.
[214] Walpole to Montagu, 26 May, 1748.
[215] Gray to Chute, July 1745 (Gray’s Works, ed. Gosse, ii.
125, ff.).
[216] Works, ed. Gosse, ii. 139.
[217] See especially Kearsley’s Strangers’ Guide (1793?).
[218] This was the number about 1793.
[219] Burney says that the first organist was Keeble, who was
succeeded by Butler. Burney himself was organist in 1770.
[220] Boswell, Life, chap. xxvi. p. 236, ed. Croker.
[221] Life, 1777–1778, chap. lxi. p. 561, ed. Croker.
[222] In the early days, sometimes one shilling and two
shillings, including the breakfast and the morning concert. On
special nights when fireworks were displayed, the price was
raised to three shillings or more. Tickets costing from half a
guinea to two guineas were issued for the masquerades.
[223] Sometimes it was advertised as open “every evening.”
People were allowed to walk in the gardens and view the Rotunda
during the day-time for one shilling.
[224] “Harlequin in Ranelagh,” London Magazine, May 1774.
[225] Cp. Gent. Mag. 1764, p. 247.
[226] Ranelagh House: a satire, 1747.
[227] London Magazine, 1774.
[228] Other early vocalists were:—Mrs. Storer (1751); Miss
Young (1755); Miss Formantel (Ten favourite songs sung by Miss
Formantel at Ranelagh, music by Mr. Oswald, published July
1758).
 [229] According to a statement of Burney’s (note in Croker’s
ed. of Boswell’s Johnson, p. 143, anno “1763”), the salt-box song
was sung by Beard accompanied on that instrument by Brent, the
fencing master, while Skeggs played on the broomstick as
bassoon. Croker assigns the composition, and apparently the first
performance, of the Ode to 1769, and states that the first edition
(which he himself had seen) of it bears the date 1749, a date
which he considered to be a misprint for 1769. But the date 1769
is, as some later writers have seen, clearly erroneous, and the
composition—and possibly the first performance at Ranelagh—
must be assigned to 1759. The published edition of the Ode, in
the British Museum, is dated (May) 1763, and the Ode was
undoubtedly performed at Ranelagh on 10 June of that year
(1763). (See Annual Register; Lloyd’s Evening Post, 8–16 June,
1763.)
[230] Cp. Six new English songs composed by Ferdinando
Tenducci, and to be sung by him at Ranelagh. Sold by the author
at his lodging in the Great Piazza, Covent Garden, 1763 (W.
Coll.).
Other performers at this period were:—1762: Champness,
Hudson, Miss Thomas, Miss Brent. 1763: Dearle, Miss Wright,
Miss Brent. 1765 (?): the elder Fawcett.
[231] Gent. Mag. 1767, p. 277.
[232] Walpole’s Letters, ed. Cunningham, ii. 150, ff. (Walpole to
Mann, 3 May, 1749).
[233] It is to be feared that this advertisement was an invention
of the editor’s, but it would have had little point for his readers had
it not been actually based on familiar incidents of the Ranelagh
masquerades.
[234] Mrs. Baddeley also sang there in 1772.
[235] An impetus to the fireworks seems to have been first
given by Angelo, father of Henry Angelo, who directed the
displays in 1766. In 1771 the fireworkers were Clitherow and
Caillot.
[236] The admission ticket for the Regatta Ball (Lake scene)
was prepared by Cipriani and Bartolozzi.
[237] Evening Mail, Feb. 15–17, 1792.
 [238] Newspaper cutting [W. Coll.] assigned to 28 June
(referring to 27 June), 1793. Mr. Vizetelly (Chevalier D’Eon, p.
322) states that D’Eon fenced at Ranelagh in 1794. The
managers of Ranelagh had given the Chevalier, who was then in
money difficulties, a benefit night in 1791 (24 June).
[239] Another great fête of this period (June 1802 or 1803?)
was the Ball given by the Spanish Ambassador.
[240] The European Magazine, October 1802, and several
newspapers of the time.
[241] The name was spelt Strumbels, Strombels and
Strumbello. Davis (Knightsbridge) calls it Stromboli House.
[242] O’Keefe’s Recollections.
[243] Davis’s Knightsbridge. Strumbelo is marked in the map of
1789 in Fores’s New Guide.
[244] The Star and Garter was at the end of Five Fields Row. In
Faulkner’s time (Chelsea, ii. p. 354), about 1829, the house, no
longer used as a tavern, was Mr. Homden’s Academy.
[245] On the Cherokee Chiefs, see Forster’s Goldsmith, bk. iii.
chap. vi. (ann. 1762).
[246] John Coan, “the unparalleled Norfolk Dwarf,” died there
16 March 1764 (Daily Advertiser, 17 March, 1764).
[247] The Dwarf’s Tavern according to Faulkner (Chelsea, ii.
354), was situated in Chelsea Fields “on the spot which was
afterwards called Spring Gardens, between Ebury Street and
Belgrave Terrace,” and which was subsequently (a few years
before 1829) occupied by Ackerman’s Waterproof Cloth
Manufactory. This Spring Garden is the place usually marked in
the maps (e.g., Horwood’s Plan, B. 1795) as the New Spring
Gardens, Chelsea, and was a place of public entertainment, as
may be inferred from a newspaper advertisement of January
1792: “J. Louis, of New Spring Gardens, Chelsea, having fitted up
likewise the above house (i.e. York Coffee House) in Norris
Street, Haymarket, for the winter, serves dinners and suppers
there.”
This Spring Garden was distinct from the Spring Gardens,
Knightsbridge, a place frequented by Pepys, and perhaps
identical with the World’s End, Knightsbridge (see Davis’s
Knightsbridge, p. 149, ff.). The Knightsbridge Spring Gardens
(which stood about where William Street joins Lowndes Square)
ceased to be a place of entertainment before 1773, in which year
the house belonging to them was occupied by Dr. C. Kelly, who
had his anatomical museum there. Walford (v. 18) engraves from
a drawing in the Crace Collection a view of the “Spring Gardens,”
which he assigns to the Knightsbridge Spring Gardens, but it is
possibly a representation of the Chelsea Spring Gardens.
[248] O’Keefe’s Recollections, vol. i. p. 88: “1762. At Cromwell
House, Brompton, once the seat of Oliver, was also a tea-garden
concert.”
[249] The price appears on the (undated) pewter and brass
admission tickets to Cromwell’s Gardens. The British Museum
has four specimens in pewter, with Cromwell’s head; and one of
the brass tickets.
[250] The Sunday Rambler visits the gardens between 7.30
and 9 p.m.
[251] I follow the Modern Sabbath, ed. 1797, in stating that
Cromwell’s Gardens were identical with the Florida Gardens. In
the second edition of the Sunday Ramble (1776) Cromwell’s
Gardens at Brompton are described under that name, and in the
1797 ed. (A Modern Sabbath) almost the same description is
repeated, and it is expressly stated that the name of the place
had been changed from Cromwell’s to Florida Gardens. On the
other hand, Faulkner describes the Florida Gardens as having
been originally a nursery garden kept by “Hyam” (he is called
Hiem in the advertisements) and converted by him (for the first
time, it is implied) into a place of public amusement. Faulkner
after describing Hale House, mentions Cromwell’s Gardens as a
separate place of amusement earlier than the Florida Gardens.
The contemporary authority of the Modern Sabbath seems,
however, preferable; especially as Faulkner does not appear to
be able to state the precise site of Cromwell’s Gardens. A further
complication may perhaps be thought to be introduced by the
passage in O’Keefe (cited in Note 1) where Cromwell’s Gardens
are described as “at Cromwell House” (i.e. Hale House). But the
inhabitants of Cromwell House from 1754 to 1794, or later, are
well known to have been people of substance, and the gardens
proper of Hale House could hardly have been employed as a tea-
garden. The Florida Gardens (afterwards occupied by Canning’s
Gloucester Lodge) were (as stated above) adjacent to Hale
House, and may possibly at one time have belonged to its
owners, and have been let out partly as a tea-garden and partly
as a nursery. The writer of the Modern Sabbath in fact remarks
that Cromwell’s Gardens is supposed to have taken its name from
the ground being formerly the patrimonial estate of the Protector
who once had a palace here upon the site of which is a
handsome seat (i.e. Hale House). The change of name from
Cromwell to Florida took place (as appears from the various
editions of a Sunday Ramble) at some time between 1776 and
1797. I suggest that the change took place about 1780, because
Lysons (who, however, does not mention Cromwell’s Gardens)
says that the place was “much puffed in the daily papers between
the years 1780 and 1790 by the name of Florida Gardens.” In any
case they certainly were advertised by Hiem as the Florida
Gardens as early as 1781.
[252] The Florida Gardens are described as a place of
entertainment in the Modern Sabbath, published in 1797, but they
were already in the possession of the Duchess of Gloucester in
September 1797. Cp. a newspaper paragraph of 25 September,
1797, in “Public Gardens” Collection in Guildhall Library: “Florida
Gardens, at present in the possession of the Duchess of
Gloucester, were fitted up in an elegant manner as a place of
resort by the late Mr. Wilder [a successor of Hiem?] but did not
answer the purpose for which they were intended.”
[253] These checks in copper and lead resemble the
tradesmen’s halfpenny tokens of the end of the eighteenth
century, and are usually described as tokens: see descriptions in
Sharpe’s Catalogue, p. 89; Atkins, p. 193. Miss Banks, in the MS.
catalogue of her tokens (p. 210) now in the Department of Coins,
British Museum, says respecting the leaden check: “One shilling
was paid on going in, and this ticket given in exchange which
would count for sixpence if the person chose liquor.”
[254] Smith’s Book for a Rainy Day: the description strictly
applies to the year 1795; A Modern Sabbath, chap. ix. (1797),
implies that the place was more refined than Smith’s description
would suggest.
[255] Blewitt lived in Bermondsey Square, where he died in
1805.
[256] Cp. “X” in The Musical Times for October 1, 1893, p. 588.
[257] It is possibly worth while to record the names of some of
the forgotten performers at Bermondsey Spa. Circ. 1785–1788
the vocalists were Mr. Birkett, Mr. C. Blewitt, Mr. Burling (or
Birling), Mr. Harriss; Mrs. Thompson, Mrs. Byrn, Mrs. Piercy; Miss
Stephenson, Miss Pay, Miss Cemmitt; Mme. Floranze. In 1792
the leader of the band was Mr. Peile, and the vocalists were Mr.
Burton, Mr. Milward, Mrs. Freeman, and Mrs. Peile.
Among the burlettas (1785–1788) were “The Quack Doctor,”
“The Fop,” and “The Auctioneer.”
[258] The fireworks in 1792 were by Rossi and Tessier, of
Ranelagh. On 25 September, 1792, “by particular desire, the
Battle of the Fiery Dragons, and the line comet to come from the
Rock of Gibraltar and cause the Dragons to engage.”
[259] This entertainment was probably first introduced in 1786,
in which year (2 September) the Public Advertiser announces “the
representation of the storming of a fort which with the fortifications
cover (sic) 3 acres of ground, the rock being fifty feet high and
200 feet long.” From about 1789 to 1792 it was advertised as a
representation of the Siege of Gibraltar. The writer of A Modern
Sabbath (1797) gives further details. “On the north-east side of
the gardens is a very fine lawn consisting of about three acres,
and in a field parted from this lawn by a sunk fence is a building
with turrets, resembling a fortress or castle.” At each side of this
fortress at unequal distances were two buildings, from which on
public nights bombshells, &c., were thrown. The fire was returned
and the whole exhibited the “picturesque prospect of a siege.”
[260] Gent. Mag. 1800, pt. i. p. 284. Keyse’s house was a large
wooden-fronted building, consisting of square divisions in
imitation of scantlings of stone (J. T. Smith). The entrance to the
Gardens was next to the house, beneath a semi-circular awning.
[261] Hughson’s London, vol. v. (1808), p. 60. The Picture of
London for 1802 mentions in the “Almanack of Pleasures” under
July 17, “A silver cup run for at Spa Gardens, Bermondsey, by
gentlemen’s ponies.”
[262] Blanchard in Era Almanack, 1870, p. 18 (followed by
Walford). Brayley and Mantell (Surrey, iii. 200, 201) say the
Gardens were closed about 1805. Lambert in his London (iv. 140)
published in 1806, speaks of the Spa as still open, but the
passage may have been written a year or more before the date of
publication.
[263] Picture of London, eds. 1802, 1829; Tallis’s Illustrated
London, ed. Gaspey.
 [264] In the Era Almanack, 1871, p. 6, it is stated that the
gardens “disappeared in 1869.” Walford, vi. 138, says they
ceased to exist in 1881.
[265] “The principal site of Finch’s Grotto Gardens appears to
have been a triangular piece of ground forming the western side
of St. George’s Street, Southwark, and bounded on the south by
the road called Dirty Lane and on the north by a vinegar yard in
Lombard Street, and the extremity of St. Saviour’s Parish.”
Wilkinson, Londina. A way from Falcon Stairs through Bandy Leg
Walk (now Guildford Street) led directly to the place, and
Williams, Finch’s successor, made an entrance from St. George’s
Fields. Those who came by water landed at Mason’s Stairs.
[266] Goldsmith’s She Stoops to Conquer, act. ii.
[267] The Dukes of York and Gloucester, brothers of George
III., are, however, said to have visited the gardens many times.
[268] List of performers under Finch and Williams:—Messrs.
Oldfield (or Offield?, 1765), Lauder, Dearle, Baker, Barnshaw of
Covent Garden Theatre, Moore, Tom Lowe, Kear (sang at
Marylebone 1754, and at Sadler’s Wells in 1771 and later),
Nepecker, Clarke, Thomas and A. Smith from the Richmond
Theatre, Weston from Drury Lane (1772), Aitken and Murphin,
Master Adams, Master Suett (in 1771, from Ranelagh, supposed
to be Dick Suett the actor), Master Green, and Master Lyon. The
female singers were Mrs. Forbes, Reed, Smith, Taylor, Clark, and
Dorman, and Misses Garvey, Thomas (in August 1765), Carli,
Moyse, Snow, Dowson (sang at Sadler’s Wells 1775), Cantrell,
Marshall, and Oakes. The instrumentalists included Cocklin and
Smart, violins; Hudson, organ; Palmer, flute.
[269] “Linco’s Travels” was also performed at the Patagonian
Theatre, Exeter Change. Humphreys’s Memoirs of Decastro, 237.
[270] A programme of a benefit night for 12 September, 1771
(under Williams), may be inserted as a specimen:—
“Act i.—An Overture. A favourite song from the opera of
Pharnaces: ‘Swift wing’d vengeance nerves my arm,’ by Mr. A.
Smith, set by Mr. Bates. A favourite Scotch air by Miss Dowson,
words and music by Mr. A. Smith. An overture by Abel. The Act to
conclude with a celebrated song from Anacreon, set by Mr.
Starling [Sterling?] Goodwin, by Mr. A. Smith. Act ii.—‘The soldier
tired of war’s alarm,’ by Miss Dowson. A new song, ‘O what a
charming thing is a battle,’ by Mr. Barnshaw. An overture in Otho,
Handel. ‘Sweet Echo,’ by a young gentleman from Italy. Trumpet
Concerto by Master Green, pupil of Mr. Jones. The celebrated
song of the ‘British Wives,’ by Mr. A. Smith. A new song by Miss
Dowson. Concerto on the violin by Mr. Smart. The Act to conclude
with ‘Russel’s triumph,’ by Mr. A. Smith, by particular desire. To
which will be added an entertainment called ‘The Gamester,’ to be
sung by Mr. A. Smith, Mr. Barnshaw, Miss Dowson, and Mrs.
Dorman, with a hornpipe in the character of a sailor, by Mr.
Rawlins from the Opera House in the Haymarket. At the end of
the hornpipe Mr. A. Smith will sing the celebrated song of ‘The
storm or the danger of the sea,’ in character. After which will be
displayed a Grand Transparent Painting.”
[271] In 1827 this stone was used as a step in the yard of the
house of a Mrs. Stevens near the site of the Gardens, the verses
being then almost illegible (Wilkinson).
[272] Nichols’s Lambeth, 1786 (in vol. ii. of Bibl. Topog. Brit. p.
77, ff.); Michaelis’s Ancient Marbles in Great Britain, 35–37.
[273] Prologue to Mrs. Centlivre’s Busybody.
[274] Chappell (Popular Music in the Olden Time, ii. 727, 728)
gives words and music.
[275] The gardens were closed on the Sundays of 1752.
[276] Gent. Mag. 1740, 525.
[277] Walpole’s Letters, ed. Cunningham, ii. 32, 24 June, 1746.
Bad company was not unknown in the earlier days of the
gardens: see Welsted’s Epistle on False Fame, 1732:—

“For Cupid’s Bowers she hires the willing scull ...

While here a ’prentice, there a captain bites.”

[278] The Complete Letter-writer, Edinburgh, 1773, quoted in

Notes and Queries, 7th ser. ii. 469.
[279] Twelve songs by Lewis Granom, as sung at Cuper’s
Gardens by Miss Maria Bennett, published London, 24
November, 1752.
[280] The fireworks at Cuper’s in 1751 are described in the
London Daily Advertiser for 10 September, 1751.
[281] ‘The Inspector,’ No. 448, in the London Daily Advertiser
for 6 August, 1752. The details that follow are derived from the
same journal for 4 August, 1752, where they are related of “one of
the public gardens on the other side of the water.” Possibly
Vauxhall is intended, but if not literally true of Cuper’s Gardens,
they seem sufficiently applicable to them.
[282] Boswell, Life of Johnson, ed. Croker, chap. xli. p. 366.
[283] Nollekens, ii. 201.
[284] The Folly was occasionally moored off the Bank side
(Wheatley, London Past and Present, “The Folly”).
[285] Amusements Serious and Comical, part ii. “The Thames.”
[286] Pepys (Diary, 13 April, 1668) jots down in his daily
expenditure a shilling spent “in the Folly.” From the circumstance
that he makes no special comment on the place it may perhaps
be inferred that he was already acquainted with it from previous
visits.
[287] Tom D’Urfey, A Touch of the Times, 1719.
[288] Walford, iii. 290, 291.
[289] Walford’s statement (Old and New London, vi. 388) that
they adjoined Cuper’s Gardens is not quite accurate. Four strips
of land belonging to four different proprietors are marked in the
map in Strype’s Stow (1720) as lying between the Belvedere
Gardens and Cuper’s Gardens.
[290] The proprietor, William Hagley, issued a halfpenny token
“at ye Restoration in St. George’s Feilds.” Boyne’s Trade Tokens
of the Seventeenth Century, ed. Williamson, p. 1036, No. 357.
[291] Advertisement in the Country Journal or the Craftsman,
31 March, 1733, where the celebrated “Purging Spring” and the
Chalybeate Spring “lately discovered” are mentioned, “at Mr.
Lewis’s, commonly called the Restauration Gardens in St.
George’s Fields.”
[292] The water was also to be obtained at a corkcutter’s under
Exeter Change in the Strand.
[293] Loudon’s Arboretum et frut. Brit. vol. i. p. 75. Nichols,
Parish of Lambeth, p. 84, says “about the year 1777.”
[294] Notes and Queries, 7th series, xi. p. 87 (communication
from Lieut.-Col. Capel Coape).
[295] This appears from the evidence brought forward in the
prosecution of Grist; see The Whitehall Evening Post for May 7 to
May 10, 1796 (referring to May 7).
 [296] Newspapers cited by E. M. Borrajo in Notes and Queries,
7th ser. xi. 138.
[297] “The English translator of Lamotte’s Life says she fell
from the leads of her house, nigh the Temple of Flora,
endeavouring to escape seizure for debt, and was taken up so
much hurt that she died in consequence. Another report runs that
she was flung out of window.... Where the Temple of Flora was, or
is, one knows not” (Carlyle, Diamond Necklace, note near end).
The Temple of Flora alluded to was certainly in London, and there
can be no reasonable doubt that the popular resort now described
is the place in question.
[298] At the period when the gardens were open “The Asylum”
(i.e. Female Orphan Asylum) stood where Christ Church now
stands.
[299] Cp. Wilkinson, Londina Illust. vol. ii. “Pantheon Theatre.”
[300] Allen (History of Lambeth, 319) states that the Apollo
Gardens were suppressed about 1791, but this is certainly
erroneous, as the gardens were frequently advertised in 1792.
Kearsley’s Strangers’ Guide to London (1793?) mentions the
place as “the resort of company in the evenings,” and says that
music was occasionally performed there. The Temple of Apollo
was described about 1796–7 in A Modern Sabbath as already
becoming ruinous, and it is there stated that Claggett, the
proprietor, had become bankrupt. A newspaper paragraph of
December 1796 refers to a field opposite the Asylum, close by
“the ditch that encircles that place of late infamous resort, the
Apollo Gardens.”
[301] This was probably the orchestra that seems to have
stood in the centre of the gardens and not that in the concert
room.
[302] Cp. a token of 1651 (“At the Dogg and Ducke in
Southwarke,” type, Spaniel with Duck in mouth) in Boyne’s Trade
Tokens, ed. Williamson, p. 1022, there assigned to The Dog and
Duck in Deadman’s Place, Southwark, by Mr. Philip Norman, who,
however, suggests the possibility of its belonging to the Dog and
Duck in St. George’s Fields. A specimen is in the British Museum.
[303] The ponds are marked in Rocque’s Map, circ. 1745. The
duck-hunting probably took place at an early period, not later than
circ. 1750.
 [304] Newspaper cutting of 1731 (W. Coll.): see also The
Country Journal or the Craftsman for 12 Aug. 1732; also 26 Aug.
1732.
[305] Johnson to Mrs. Thrale, 10 July, 1771, Letter viii. in
Johnson’s Works (ed. Murphy), xii. 338.
[306] A specimen in British Museum (from Miss Banks’s Coll.).
Silver, size 1·25 inch; Obverse: Lazarius Riverius.—Non omnibus
dormio.—Miseris succurrere disco. Bearded head of Rivière, to
left; beneath head, the number “18” incised. Reverse: The original
Spaw in St. George’s Fields so memorable in the Plague, 1665.—
For the proprieters (sic) T. Townshend Alchemist to his Majesty,
1760. Another specimen described in C. A. Rudolph’s Numismata
(relating to medical men), 1862, p. 45, has the words “Robert
Baker, Esq., Twickenham,” evidently the subscriber’s name,
engraved on the edge.
[307] The water continued to be advertised in newspapers of
1771–1779. Hedger afterwards put in his nephew Mills (or Miles)
to conduct the house which is said to have yielded Hedger £1,000
a year, but evidently himself remained the moving spirit.
[308] On the “Maid of the Oaks,” see Baker’s Biog. Dram.
[309] The Dog and Duck may have been more respectably
conducted for a time. On 28 May, 1792, a charity dinner of the
Parish of St. Thomas, Southwark, was held there (engraved
invitation ticket in W. Coll.).
[310] The Dog and Duck and the Apollo Gardens were for a
time within the Rules of the King’s Bench Debtors’ Prison (De
Castro’s Memoirs, pp. 126, 134).
[311] In De Castro’s Memoirs (1824) it is stated that he died
“about two years ago,” which indicates the year 1822, or possibly
the year 1810 (for part of the Memoirs were apparently written
circ. 1812) as the date of his death. He was certainly alive,
however, during part of the year 1810.
[312] Lambeth Wells are marked in the map of 1755 in Stow’s
Survey.
[313] They were of smaller extent than the Cumberland
Gardens, their river-side neighbour situated a little further south.
[314] One account calls him Nathan Hart.
 [315] “Riley’s Gardens, Vauxhall,” mentioned in Trusler’s
London Adviser, 1786, are doubtless identical with Reilly’s
Cumberland Gardens.
[316] In the Picture of London for 1829 the Cumberland
Gardens are named in the list of places of London amusement,
but it is probable that this entry has been inadvertently copied
from a previous edition (1823) of the work. Cp. Allen, Lambeth
(1827), p. 379.
[317] Timbs (Curiosities of London, 1868, p. 18) says that
Price’s Candle Manufactory occupied the site, but in the Post
Office Directory map of 1858 the “Phœnix Gas Works” are
marked immediately south of Vauxhall Bridge and the Candle
Works still further south, i.e., beyond the Vauxhall Creek which
formed the southern boundary of the gardens.
[318] In the advertisements the name Vauxhall Gardens first
appears in 1786, but many years before that date the place was
often popularly known as Vauxhall Gardens.
[319] The place was at first generally called The New Spring
Garden. Cunningham (Handbook of London, s.v. “Vauxhall
Gardens”) and other modern writers suppose that it was called
New to distinguish it from the old Spring Garden at Charing
Cross, and this view seems to receive some countenance from a
passage in Evelyn’s Fumifugium, 1661, quoted by Cunningham. It
must be borne in mind, however, that there existed at Vauxhall
shortly after the Restoration, two Spring Gardens which seem to
have been distinguished as the Old and New. This appears very
distinctly from the following passage in Pepys, under date 29 May,
1662:—“Thence home and with my wife and the two maids and
the boy took the boat, and to Foxhall, where I had not been a
great while. To the Old Spring Garden, and there walked long,
and the wenches gathered pinks. Here we staid, and seeing that
we could not have anything to eate but very dear, and with long
stay, we went forth again without any notice taken of us, and so
we might have done if we had had anything. Thence to the new
one, where I never was before, which much exceeds the other;
and here we also walked, and the boy crept through the hedge
and gathered abundance of roses, and after a long walk, passed
out of doors as we did in the other place.”
Somewhat earlier (2 July, 1661), Evelyn in his Diary has the
entry “I went to see the New Spring Garden at Lambeth, a pretty
contrived plantation.” This probably, if not quite certainly (for