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Research Progress in Structure-Activity Relationship of Bioactive Peptides

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JOURNAL OF MEDICINAL FOOD
J Med Food 00 (0) 2014, 1–10
REVIEW ARTICLE
# Mary Ann Liebert, Inc., and Korean Society of Food Science and Nutrition
DOI: 10.1089/jmf.2014.0028

Research Progress in Structure-Activity Relationship of Bioactive Peptides

Ying Li1,2 and Jianmei Yu1
1
Department of Family and Consumer Sciences, North Carolina A&T State University, Greensboro, North Carolina, USA.
2
Institute of Agricultural Products Processing, Jiangsu Academy of Agricultural Science, Nanjing, Jiangsu, China.

ABSTRACT Bioactive peptides are specific protein fragments that have positive impact on health. They are important
sources of new biomedicine, energy and high-performance materials. The beneficial effects of bioactive peptides are due to
their antioxidant, antihypertensive, anticarcinogenic, antimicrobial, and immunomodulatory activities. The structure-activity
relationship of bioactive peptides plays a significant role in the development of innovative and unconventional synthetic
polymeric counterparts. It provides the basis of the stereospecific synthesis, transformation, and development of bioactive
peptide products. This review covers the progress of studies in the structure-activity relationship of some bioactive peptides
including antioxidant peptides, angiotensin-I-converting enzyme-inhibitory peptides, and anticarcinogenic peptides in the past
decade.

KEY WORDS:  anticancer  antihypertensive  antioxidant  bioactive peptides  structure-activity relationship

INTRODUCTION Pro-Ala-Ala-Pro synthesized on the basis of solid phase

peptide synthesis using ASP48S is an artificial peptide.5
B ioactive peptides are short sequences of approxi-
mately 2–20 amino acids in length that exert physio-
logical benefits when consumed in vivo. They are inactive
Antihypertensive drugs such as Captopril, Enalapril, and
Fosenpril used now are all synthetic peptides. According to
the physiological functions, bioactive peptides can be di-
within the sequence of the parent proteins and may be released
vided into antihypertensive peptides, antioxidant peptides,
by proteolytic hydrolysis using commercially available en-
antimicrobial peptides, anticancer peptides, immunomodu-
zymes or proteolytic microorganisms and fermentation meth-
latory peptides, opioid peptides, mineral binding peptides,
ods.1 Bioactive peptides can be absorbed in the intestine and
antithrombotic peptides, thymosin, hypnosis peptide, neu-
enter the blood stream directly, which ensures their bioavail-
ropeptides, and so on.6,7
ability in vivo and a physiological effect at the target site.2
In recent years, consumer interest in the relationship be-
There are wide varieties of bioactive peptides in the na-
tween diet and health has increased substantially. It has been
ture and nearly thousands of bioactive peptides have been
recognized that functional foods may make a positive con-
discovered. According to their forming process, bioactive
tribution to health and well-being when combined with a
peptides can be divided into endogenous and exogenous
healthy lifestyle. Food-derived bioactive peptides exerting
bioactive peptides. The endogenous peptides are the pep-
physiological effect in humans have attracted more attention
tides hydrolyzed from protein by endopetidase, and the
by either consumers or scientists. The food-derived bioactive
exogenous peptides are the peptides hydrolyzed from pro-
peptides are found in milk, egg, meat, and fish of various
tein by exopeptidase. According to the materials from which
kinds and in many plants.8 It has been found that the addition
bioactive peptides are produced, they can be divided into
of appropriate active peptides in the diet is very beneficial to
marine and terrestrial bioactive peptides. According to their
human health because they can regulate physiological func-
origin, they can be divided into natural and artificial bio-
tions.9 Depending on their amino acid sequences, food-
active peptides. For instance, antioxidant peptides isolated
derived peptides can exhibit diverse activities, including
from rapeseed proteins3 and angiotensin-I-converting en-
opiate-like, mineral binding, immunomodulatory, antimicro-
zyme (ACE) inhibitory peptides Gly-Pro-Leu and Gly-Pro-
bial, antioxidant, antithrombotic, hypocholesterolemic, anti-
Met extracted from the skin of Theragra chalcogramma4
cancer, and antihypertensive actions.10 Moreover, many milk
are natural peptides, while antioxidant peptide Trp-Tyr-
or milk protein-derived peptides exhibit multifunctional
properties.11 Some bioactive peptides as functional foods
Manuscript received 13 February 2014. Revision accepted 18 June 2014. have been in commercial process, especially in Japan.12 Ex-
amples are low antigen food, mobile food, baby products,
Address correspondence to: Jianmei Yu, PhD, Department of Family and Consumer
Sciences, North Carolina A&T State University, 1601 East Market Street, Greensboro,
food products for sports nutrition, blood pressure regulation,
NC 27411, USA, E-mail: jyu@ncat.edu calcium-absorption promotion, and other products.

1
2 LI AND YU
Bioactive peptide with specific physiological activity is
composed of certain amino acid residues linked in specific
sequences. The activities or functions of the bioactive pep-
tides depend on their structures, such as the amino acid
composition, the type of amino acid in C- and N-terminal,
the length and weight of the peptide chain, the hydrophobic
property, charge character of amino acid, spatial structure,
and so on.13 The relationship between activity and structure
of peptide is still in the exploratory stage. Further exploring
the structure-activity relationship and revealing the mecha-
nism of bioactive peptide will provide important theoretical
basis for synthesis, transformation, development of bioac-
tive foods, or complementary medicines. In this review, the
available information regarding the relationship between
structure and activity of bioactive peptide was summarized.
The antihypertensive, antioxidative, and anticarcinogenic
mechanisms of different bioactive peptides were also cov-
ered in this review.
STRUCTURE-ACTIVITY RELATIONSHIP
OF ACE INHIBITORY PEPTIDES
Hypertension refers to arterial systolic and/or diastolic
blood pressure increased ( ‡ 140/90 mmHg) in the resting
status. It is a systemic disease characterized by organ re-
modeling, often accompanied by fat and glucose metabo-
lism disorder, and heart, brain, kidneys, retina, and other
organs functional changes.14 At present, hypertensive dis-
eases endanger human health seriously. The average prev-
alence rate of hypertension is about 15% worldwide.15
Human body’s blood pressure is regulated by many fac-
tors. The most important one is the balance of boost system
(Renin-Angiotensin System, RAS) and depressurization
system (Kallikrein-Kinin System, KKS). RAS and KKS is a
pair of mutually antagonistic systems in blood pressure
regulation, in which, the ACE (EC 3.4.15.1) balance the
boost and depressurization system as a rate-limiting en-
zyme. In RAS system, renin stimulates angiotensinogen to
release a nonactive peptide-angiotensin I. ACE catalyzes
angiotensin I (10 peptides) into angiotensin II (8 peptides).
The latter has a strong vasoconstrictor and boost effect,
leading blood volume and blood pressure increased.16 In the
KKS system, ACE acts on the vasodilator bradykinin Phe-
Arg or Ser-Pro at C-terminal and is inactivated, causing high
blood pressure.17 If ACE activity is inhibited, biosynthesis
of angiotensin II is reduced and the bradykinin is in-
activated. Subsequently, blood pressure goes down. There-
fore, ACE becomes an ideal target for the treatment of
hypertension disease.
By now, more than 16 kinds of ACE inhibitors such as
captopril, enalapril, benazepril, and cilazapril are officially
used for clinical treatment of hypertension and 80 kinds
have been studied.18 Most of these drugs are synthetic drugs,
often accompanied by many side effects such as cough,
pruritus, taste disorder, or low blood pressure. Many studies
confirm that a reasonable diet can prevent and relieve hy-
pertension.19,20 Therefore, more attentions are on finding
and developing safe, nontoxic, and efficient alternative an-
tihypertensive drugs from food sources. It has become a
research hotspot.
There is a class of peptides with good ACE inhibitory
activity from food sources. Normally, these peptides are in
relative small molecular weight.21–23 The amino acid se-
quence and chain length of these peptides have different
characteristics. Only when it combines with ACE active site
closely, ACE inhibitory peptides can show inhibitory activity.
The catalytic site of ACE is composed of three subunits,
which are corresponding to three hydrophobic amino acids
(Pro, His, and Phe) of angiotensin I in C-terminal district. It
catalyzes angiotensin I into bradykinin and leads to blood
pressure rise. Therefore, the three amino acids in C-terminal
district of bioactive peptides greatly influence ACE activity.
Amino acids composition and ACE inhibitory activity
The primary structure and amino acid composition of ACE
inhibitory peptides are closely related to its inhibitory activ-
ity. Research showed that the interactions between peptides
and ACE were greatly influenced by the sequences of three
amino acids in C-terminal district of peptides.24,25 Aromatic
or alkaline amino acids in N-terminal of ACE inhibitory
peptides can improve its ACE inhibitory activity. It was also
reported that the peptides containing leucine, isoleucine, and
valine in N-terminal exhibited good antihypertensive effect,
but the ACE inhibitory activity was lowered in the presence
of proline in N-terminal of ACE inhibitory peptide.
Two hundred seventy ACE inhibitory peptides were
collected and their amino acid compositions were ana-
lyzed.26 The amino acids tyrosine (Tvr), proline (Pro),
tryptophan (Trp), phenylalanine (Phe), and leucine (Leu) are
more likely in the C-terminal of these ACE inhibitory
peptides while arginine (Arg), Tvr (Gly), glycine, valine
(Va1), alanine (Ala), and isoleucine (Ile) are more likely in
the N-terminal. The characteristics of C-terminal amino
acids contribute more to the antihypertensive effects.
Therefore, the activity of ACE inhibitory peptide is closely
related to the terminal amino acid composition.
Hydrophobicity/hydrophilicity of peptide and ACE
inhibitory activity
The hydrophobic/hydrophilic property of polypeptide is
another important factor influencing its activity. There is a
positive correlation between hydrophobicity of C-terminal
amino acids and ACE inhibitory activity.27,28 The high hy-
drophilicity makes the peptide hardly close to the ACE ac-
tive sites and results in the weaker activity. The relationship
between mass percentage of hydrophobic amino acids in C-
terminal tripeptides and ACE inhibiting activity is shown in
Table 1. It can be seen that there is a large amount of hy-
drophobic amino acids in the primary structure of ACE in-
hibitory peptides, especially in C-terminal tripeptides. The
relationship between content of hydrophobic amino acids and
ACE inhibitory activity showed that most of the antihyper-
tensive effect of ACE inhibitory peptides was in accordance
with the law above. In addition, studies also show that N-
terminal hydrophobic amino acid or aliphatic amino acids in
 STRUCTURE-ACTIVITY RELATIONSHIP OF BIOACTIVE PEPTIDES 3

Table 1. Relationship Between Percentage living organisms, but the free radicals produced by oxida-
of the Hydrophobic Amino Acids in C-Terminal Tripeptide tion could be very destructive. The attacks of free radicals
and Angiotensin-I-Converting Enzyme Inhibitory Activity lead cells to continuous damage, known as oxidative stress
Hydrophobic amino
or oxidation.41 Under normal circumstances, oxidation is a
acids in C-terminal IC50 dynamic balance between continuous emergence and elim-
Sequence tripeptide (%) (lM) Reference ination of free radicals in vivo. The excessive free radicals
would cause oxidation damage of cell tissues, which leads to
AHLL 67 40.2 18 human aging and many other diseases, such as cancer, high
RYLGY 67 0.71 30
LIWKL 67 0.47 31 blood pressure, artery hardening, inflammation, and infer-
YPHK 33 2.31 32 tility. Heart, lungs, and brain are the main targets of free
VKAGF 100 20.3 33 radicals because they are heavy users of oxygen.
DERF 33 37.08 34 Oxidation in foods is one of the major causes of food
RYPSYG 33 65.71 34 deterioration.42 It affects lipids, proteins, and carbohydrates.
NGTWFEPP 67 0.63 35 However, lipid oxidation is the main cause of deterioration
LVYPFPGPIPNSLPQNIPP 100 5 36
VAP 100 5.34 37
of food quality, leading to rancidity and shortening of shelf
VYPFPGPIPNSLPQNIPP 100 4 28 life.43 Oxidation of proteins in foods is influenced by lipid
GPL 100 2.6 4 oxidation, where lipid oxidation products react with proteins
GPM 100 17.13 4 causing their oxidation.44 Carbohydrates are also susceptible
ALPMHIR 33 42.6 38 to oxidation, but they are less sensitive than lipids and
proteins.45
IC50 value: the concentration of peptide required to inhibit 50% of the
activity.
Antioxidant is a substance that significantly decreases the
adverse effects of reactive species, such as reactive oxygen
and nitrogen.46 In terms of foods, antioxidants are com-
pounds that are able to delay, retard, or prevent autooxida-
side chain can promote the peptide binding with ACE.29 We tion processes.47 At present, the antioxidants are mainly
can see from Table 1, peptides with hydrophobic amino acids from chemical synthesis, such as butylated hydroxyanisole,
in C-terminal had higher ACE inhibitory activity, but the butylated hydroxutoluene, propyl gallate, and tertiary bu-
activity did not increase with increasing percentage of hy- tylhydroquinone. They are widely used as preservatives in
drophobic amino acids. The same percentage of different food and cosmetics. Due to the potential adverse effects of
hydrophobic amino acids had different activity. IC50 of these synthetic antioxidants on the human liver, spleen,
AHLL with 67% hydrophobic amino acids of two leucine lungs, and other viscera organs, food industry has been ac-
was 40.2 lM; IC50 of NGTWFEPP with 67% hydrophobic tively seeking natural antioxidants. Natural antioxidants
amino acids of two proline was 0.63 lM. This means the widely used in foods include vitamin C, vitamin E, and
percentage of the hydrophobic amino acids in C-terminal polyphenols. In the case of vitamin C and vitamin E, the
tripeptide is not the only factor influencing the ACE inhibi- antioxidant molecule is either recharged by accepting an
tory activity, the type of amino acid in C-terminal and the electron from another type of antioxidant or it is recycled
length of peptide also play important roles. into building tissue repair.
Since Prokorny first reported that some peptides and
Positive charged amino acids in C-terminal proteins hydrolysate could reduce autooxidation rate and the
and ACE inhibitory activity peroxide content of fat in 1991, more and more research has
focused on searching for antioxidant peptides with high
Research showed that lysine(e-amino positive charge) and
antioxidant activity.48 Whey, soy, and egg yolk hydrolysates
arginine (guanidine positive charge) in C-terminal of peptide
have shown to inhibit lipid oxidation in various muscle
can promote the ACE inhibitory activity.38 Table 1 shows that
foods, such as beef, pork, and tuna.49,50 Some histidine (His)
the activity of Ala-Leu-Pro-Met-His-Ile-Arg with arginine in
containing peptides such as carnosine and anserine that are
C-terminal is stronger compared with other peptides. Also, Ala-
naturally present in skeleton muscle have antioxidant ac-
Ile-Tyr-Lys with lysine in C-terminal has higher activity.39
tivity. Most experts believe that getting antioxidant peptide
Additionally, Pro in C-terminal with strong affinity on active
from food is the most healthful way. Antioxidant peptide
site can promote the binding with ACE.40
with small molecular weight is easy to be absorbed and has
In summary, peptides with higher ACE inhibitory activity
excellent antioxidant effect. The antioxidative pathways
usually have aromatic or alkaline amino acids in N-terminal,
mainly include the active oxygen inactivation, scavenging
higher quantity of hydrophobic and positively charged
free radicals, chelating metal ions, reducing the formation of
amino acids in C-terminal.
hydrogen peroxide, and changing physical properties of
food system.51 The antioxidant activity of antioxidant pep-
STRUCTURE-ACTIVITY RELATIONSHIP
tide is related to the amino acid composition, the amino acid
OF ANTIOXIDANT PEPTIDES
sequence of the peptides, the molecular weight of the pep-
Many health problems stem from the effect of oxidation tide chain, the N- and C-terminal amino acid residues, and
process in human body. Oxidation is a vital process in all hydrophilic properties.
4 LI AND YU

Amino acid composition and antioxidant activity Hydrophobic amino acids in the side chain or C-terminal
of bioactive peptides and N-terminal of peptides display strong antioxidative ac-
tivity. It is believed that the antioxidant tripeptide will
Hydrophobic amino acids and aromatic amino acids have
present high antioxidative activity if its N-terminal is hy-
close correlation to the antioxidant activity. Generally, the
drophobic amino acids with low isoelectric point, such as
more hydrophobic amino acids is, the stronger antioxidant
Ala, Gly, Val and Leu.58 N-terminals of six antioxidant
is. The reason is that fatty acid free radicals are hydrophobic
peptides isolated from soybean protein enzymatic hydroly-
and they tend to combine with hydrophobic antioxidant
sates are all hydrophobic amino acids.59 The more hydro-
peptides first.52
phobic amino acids and aromatic amino acids the peptide
First discovered peptide with antioxidant activity was an
contained, the more significant antioxidant activity it
acidic peptide.53 There is an interactive passivation of oxi-
showed.52 The antioxidant peptides identified in recent years
dation between some metal ion (Fe2 + and Cu + ) and car-
and their hydrophobic amino acids contents are summarized
boxyl residue of side chain in acidic amino acid, which
in Table 2.
decreases the free radical chain reaction and exerts the an-
tioxidant effect. The proton donor in amino acid residues
Other factors
such as Tyr and Trp is a necessary component of antioxidant
peptide, in which, hydrogen atoms were supplied to free The correlation between the structural conformation of
radical with its hydrogen donating capacity. Finally, the amino acid of peptides and their antioxidant activity was
indole free radicals and benzene-oxygen free radical is reported. When second L-histidine in Pro-His-His was re-
stable by means of resonance. The free radical chain reac- placed by D-histidine, the antioxidant activity of the peptide
tion is thus slowed or stopped.41 Peptide Leu-Asp-Tyr-Glu decreased obviously.73 There was a close relationship be-
was an antioxidative peptide prepared from corn.54 Tyrosine tween antioxidant activity of peptides and their amino acid
in the peptide provided proton quenching free radicals and structures. Suetsuna synthetized peptides lack of Tyr, Tyr-
the carboxylate base of its adjacent aspartic acid (Asp) and Phe, Tyr-Phe-Tyr, and Tyr-Phe-Tyr-Pro based on the anti-
glutamate (Glu) possessed the electron-withdrawing effect, oxidant peptide Tyr-Phe-Tyr-Pro-Glu-Leu from casein. The
which enhanced the proton donation of Tyr. Furthermore, activities of preferred sequences were Glu-Leu (EL) > Tyr-
Leu of the N-terminal was a hydrophobic amino acid, which Phe-Tyr-Pro-Glu-Leu (YFYPEL) > Phe-Tyr-Pro-Glu-Leu
enhanced the interaction of antioxidant peptides with fatty (FYPEL) > Tyr-Pro-Glu-Leu (YPEL) > Pro-Glu-Leu (PEL),
acids and improved the capture of lipid free radical. suggesting that the EL sequence is important for the activity.74
Some amino acids have the antioxidative activity. Cy- Also, there is close relationship between molecular weight and
steine (Cys) and methionine (Met) can directly react with the antioxidant activity. Usually, the smaller the molecular
the corresponding free radicals. Met can easily be oxidized weight is, the easier that peptide goes through the biological
to Met sulfoxide, the latter can be deoxidated to Met by Met membrane to the effective site.55
sulfoxide reductase, which resume the antioxidant activity Although significant progress has been made in the
of Met. The antioxidant activity of single amino acid is far structure-activity relationship of antioxidant peptides, there
lower than that of peptide containing the amino acid.55 It is is undoubtedly still an enormous amount to be learned. At
believed that the His of the peptide can be used as a metal
ion chelating agent, active oxygen quencher, and hydrogen
free radical scavenger, which enhance the antioxidant ac- Table 2. Antioxidant Peptides and Percentage
tivity of the peptide.56 Oxidation of amino acid residues is of the Hydrophobic Amino Acids
one of the causes that antioxidant peptide could scavenge
free radicals. Although His is important to the antioxidant Hydrophobic amino
Sequence acids content (%) Reference
activity of the peptide, the free amino acid doesn’t exhibit
good antioxidant activity because the primary structure of HGPLGPL 86 60
peptides is a necessary factor of antioxidant activity. Ob- HPHPHLSF 50 61
viously, the protection of lipid from oxidation by antioxi- GSTVPERTHPACPDFN 43 62
dant peptides is at the expense of specific amino acids such PSYV 50 63
IVGGFPHYL 78 64
as His and Met in the peptides. RPDFDLEPPY 50 65
CAAP 75 66
Hydrophobic/hydrophilic amino acids VCSV 50 66
and antioxidant activity VKAGFAWTANQQLS 57 67
WYSLAMA 71 68
Nonpolar aliphatic side chain can strengthen the interac- INYW 50 69
tion between antioxidant peptides and hydrophobic poly- LDQW 50 69
unsaturated fatty acids. Peptides with hydrophobic amino ISELGW 50 70
acids such as His, Pro, Cys, Tyr, Trp, Phe, and Met delay the LPHSGY 50 71
lipid peroxidation chain reaction by combining with oxygen LLGPGLTNHA 70 72
DLGLGLPGAH 80 72
or inhibition of hydrogen release in lipid, thus producing the LPHSGY 50 71
antioxidant effect.57
 STRUCTURE-ACTIVITY RELATIONSHIP OF BIOACTIVE PEPTIDES
present, the active sites of antioxidant peptides cannot be
analyzed and confirmed accurately. There is no final con-
clusion about the relation between the molecular confor-
mation and activity of antioxidant peptides. How much the
interaction of amino acids affects the antioxidant activity
needs further illustration. With the development of bioen-
gineering and new types of separate technology, the rela-
tionship of the structure-activity of antioxidant peptides will
be more and more visualized.
STRUCTURE-ACTIVITY RELATIONSHIP
OF ANTICANCER PEPTIDES
Nearly half a century, through the tireless efforts of sci-
entists, gradually realized that cancer is caused by compli-
cated reasons including environmental, nutritional, dietary,
genetic, viral infections, and lifestyle. The occurrence of
cancer is a multifactor, multistep complex biological pro-
cess, which can be divided into three different and succes-
sive stages including initiation, promotion, and progression,
and involving a variety of complex mechanism, such as
oncogene activation, inactivation of cancer suppressor
genes, and their interactions.75 Cancer remains a major
source of morbidity and mortality throughout the world and
it is predicted to displace heart diseases as the leading cause
of death worldwide.76 In the United States, one person is
diagnosed with cancer every 30 sec and one person dies of
cancer every 35 sec.77
Although much progress has been achieved in respect of
cancer treatments and therapies in recent decades, chemo-
therapy remains the choice of usual treatment for advanced
or metastatic disease. However, the use of conventional
chemotherapeutic agents that typically target rapidly di-
viding cancer cells is often associated with deleterious side
effects due to drug-induced damage to normal cells and
tissues.78 Moreover, cancer cells develop resistance to these
drugs that is mediated by the over expression of multidrug-
resistance proteins that pump the drugs out of cells and thus
render the drugs ineffective.79 Therefore, the research and
development of more effective and less toxic anticancer
agents has become necessary. Anticancer peptides have
recently received attention as alternative chemotherapeutic
agents that overcome the limits of current drugs. These
peptides have several advantages over currently used anti-
cancer therapeutics, such as selective cytotoxicity for cancer
cells, bypass of the multidrug-resistance mechanism, and
additive effects in combination of therapy.80
Hundreds of natural peptides have been found to show
antimicrobial properties that can kill a wide spectrum of
Gram-positive and Gram-negative bacteria, protozoa, and
fungi. Some antimicrobial peptides exhibit anticancer ac-
tivity, thus called anticancer peptides.81 Because many an-
timicrobial peptides may be toxic to human being,
anticancer peptides derived from foods with less toxicity
have attracted more and more attention of researchers and
pharmaceutical industry. Kannan observed the high anti-
proliferative activity in human colon and liver cancer cells
in the low molecular weight fraction ( < 5 kDa) of an Alca-
5
lase hydrolysate from rice bran.82 A 440.9 Da anchovy hy-
drophobic peptide was found to be able to induce apoptosis
in human U937 lymphoma cells by increasing caspase-3 and
caspase-8 activity.83 Epinecidin-1, a peptide from fish
(Epinephelus coioides) showed an antitumor effect similar
to lytic peptides in human fibrosarcoma cells.84 These an-
ticancer peptides usually have cationic and small molecule.
In this regard, electrostatic interactions between cationic
anticancer peptides and anionic cell membrane components
are believed to be a major factor in the selective killing of
cancer cells. Although some researchers have suggested that
these peptides exert activity against cancer cells through
ion-permeable channel formation in the cell membrane,85
the structure-activity relationship and the precise mecha-
nism of the cancer cell-killing action of the peptides remains
to be elucidated.
Spatial structure and anticancer activity
a-helical anticancer peptides. a-helical structure is the
main structural characteristics of anticancer peptides. The
high amphipathic and stable helical regions tend to be the
heart of anticancer activity. Hydrophilic and hydrophobic
amino acid side chains are arranged in two side of a-helical
structure and form clear hydrophilic and hydrophobic sur-
faces. Or they are concentrated in the N-terminal and C-
terminal to format distinct hydrophilic and hydrophobic
sides. The amphiphilic structure is conducive for the
membrane binding of anticancer peptides.86 The anticancer
activity of alpha-anticancer peptides (a-ACPs) normally oc-
curs at micromolar levels but is not accompanied by signifi-
cant levels of hemolysis or toxicity to other mammalian cells.
Structure/function studies have established that architectural
features of a-ACPs such as amphiphilicity levels and hy-
drophobic arc size are of major importance to the ability of
these peptides to invade cancer cell membranes.87
Various structure-activity studies have been conducted on the
a-helical peptide. The 26-residue amphipathic a-helical peptide
A12L/A20L (Ac- KWKSFLKTFKSLKKTVLHTLLKAISS -
amide) with strong anticancer activity and specificity was used
as the framework to study the effects of helicity of a-helical
anticancer peptides on biological activities. Strong hemolytic
activity of peptides generally correlated with high hydropho-
bicity, high amphipathicity, and high helicity. Lower helicity
caused the decrease of anti-HeLa activity of peptides.88 In most
cases, the D-amino acid substituted peptides possessed an en-
hanced activity compared with L-diastereomers.89 Magainin 2,
N-Terminal truncation of the first 3 residues GIG does not much
influence the anticancer activity, but the residue 4 (K) from the
N-terminal is critical to the anticancer activity of magainin. The
deletion of residue 4 (K) greatly reduces activity and further
deletion of residues 5 and 6 (F and L) eliminates activity alto-
gether.90 That is because the truncated peptide is unable to span
the lipid bilayer corresponding to loss of anticancer activity. LL-
37 could interact with the alert signal and result in more NK cells
(cells of immune system) that are capable of destroying the
gastric cancer cells (Table 3). Cecropins (N-terminal a-helix of
antimicrobial protein) kill neoplastic cells at concentrations
6 LI AND YU

Table 3. Summary of Selected Cationic Amphipathic Peptides with Anticancer Activity

Peptide Sequence Reference

a-helical
LL-37 LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES 96
BMAP-28 GGLRSLGRKILRAWKKYGPIIVPIIRI 78
Temporin-1CEa FVDLKKIANIINSIFGK 97
Aureins GLFDIIKKIAESF 98
Magainin GIGKFLKKAKKFGKAFVKILKK 99
Melittin GIGAVLKVLTTGLPALISWIKRKRQQ 100
Cecropin A KWKLFKKIEKVGQNIRDGIIKAGPAVAVVGQATQIAK 101
Cecropin B KWKIFKKIEKVGRNIRNGIIKAGPAVAVLGEAKAL 101
Citropins GLFDVIKKVASVIGGL 102
b-sheet
b-defensin NPVSCVRNKGICVPIRCPGSMKQIGTCVGRAVKCCRKK 96
Anginex LHKRWKKFILIKVMKQLVNSDLKINA 103
Lactoferricin B FKCRRWQWRMKKLGAPSITCVRRAF 104
Gomesin ECRRLCYKQRCVTYCRGR 105
Tachyplesin KWCFRVCYRGICYRRCR 93
Buforin II RAGLQFPVGRLLRRLLRRLLR 85
Protegrin-1 RGGRLCYCRRRFCVCVGR 102

lower than those required to lyse normal cells such as peripheral
blood lymphocytes.91 BMAP-28 could kill various human
leukemia cell lines at 1.5–6 lM concentrations. The hydro-
phobic tail (residues 19 to 27 or 28) at the COOH-terminus is
important for BMAP peptides to mediate their cytotoxic ef-
fect.78 Melittin, a 26 amino acid channel-forming cationic am-
phiphilic peptide, specifically counter selects for cells in culture
that express high levels of the oncogene (Table 3). The structure
facilitates the formation of ion-permeable pores in membranes,
consequently inducing depolarization and cytolysis.86
tion of the Cys residue in the amino acid sequence from the
N-terminus), while in b-defensin are Cys1–Cys5, Cys2–
Cys4, and Cys3–Cys6.95 Three pairs of disulfide bonds are
important to stabilize the spatial configuration of defensin.
The structures of the two main defensin subfamilies, a and b-
defensins, were analyzed by two-dimensional NMR and X-
ray crystallography were used for analysis and both were
found consisting of a triple-stranded b-sheet. Various types of
a-helical and b-sheet anticancer peptides are summarized
below.

b-sheet anticancer peptides. b-sheet anticancer pep-
tides are generally stabilized by the disulfide bonds, char-
acterized by the presence of antiparallel b-sheets. In this
family, defensins, lactoferricin, and tachyplesin are con-
strained by disulfide bonds. Tachyplesins represent a con-
venient scaffold for structure-activity studies due to their
small size. Tachyplesin I could be against human gastric
adenocarcinoma92 and human hepatocarcinoma cells93 with
an antiparallel b-sheet (residues 3–8 and 11–16) connected
by a type I b-turn (residues 8–11) stabilized by two disulfide
bonds.94 Buforin IIb could be against 62 cancer cell lines
by specifically targeting cancer cells through interaction
with cell surface gangliosides. It deduced mitochondria-
dependent apoptosis in the cells.95 Protegrin-1 displayed
cytotoxicity in human histiocytic lymphoma cell lines
(Table 3). Bovine lactoferricin (LfcinB) consists of 25 amino
acid residues including two Cys residues that create a dis-
ulfide bond linking the highly positively charged NH2-
terminal region and the COOH-terminal region of the
peptide.56 It could kill leukemia cells, fibrosarcoma cells,
various carcinomas, and neuroblastoma cells through sup-
pressing both basic fibroblast growth factor bFGF- and
VEGF- driven proliferation and migration of human endo-
thelial cells, including a-defensins and b-defensin (Table 3).
The disulfide connections in a-defensins are Cys1–Cys6,
Cys2–Cys4, and Cys3–Cys5 (the number indicates the loca-
Anticancer peptides and cancer cell membrane. The
bilayer phospholipids of cell membrane function as a per-
meability barrier and regulate the flux of metabolites be-
tween the external environment and the intracellular
content. Therefore, membrane is the first and main factor for
the anticancer activity exertion. Cancer cell membranes
typically carry a net negative charge due to a higher than
normal expression of anionic molecules. The initial asso-
ciation of peptides with the cancer cell membrane occurs
through electrostatic interactions between the cationic pep-
tide and anionic lipopolysaccharide in the outer membrane
leading to membrane perturbation.86 The peptides associate
with the outer monolayer of the cytoplasmic membrane. If
this reorientation leads to perturbation of the integrity of the
cytoplasmic membrane, cancer cell membrane is disrup-
tive.106 The net charge and the number of positive charge
also influence the activity of peptides. There is a sharp
transition of hemolytic activity on the polar face of V13K,
the change from + 8 to + 9 resulted in greater than 32-fold
increase in hemolytic activity.107 In contrast to neoplastic
cells, electrostatic interactions between anticancer peptides
and untransformed cells are not favored because of the
overall neutral charge conferred on healthy cells by the
zwitterionic nature of their major membrane components.
Besides electrostatic interactions, molecular properties of
lipids such as their molecular shape and structural folding
 STRUCTURE-ACTIVITY RELATIONSHIP OF BIOACTIVE PEPTIDES
play a significant role for the aggregation state of lipids to
affect interactions between membrane and active peptides.108
Apart from the surface characteristics, membrane fluidity also
appears to be altered in tumorigenic cells. The increased
fluidity of the cancer cell membrane may enhance the lytic
activity of ACPs by facilitating membrane destabilization for
lymphomas, lung carcinomas, and neural tumors.109
Anticancer peptides induce cell death with different
mechanisms, including apoptosis, affecting the tubulin-
microtubule equilibrium, or inhibiting angiogenesis. Antic-
ancer peptide executes its function depends on a number of
physicochemical properties: the amino acid sequence, net
charge, amphipathicity, hydrophobicity, structural folding
(includes secondary structure, dynamics, and orientation) in
membranes, oligomerization, peptide concentration, and
membrane composition.110 They are normally characterized
by low molecular weight (in the majority of cases less than
30 amino acids) and exhibit a predominantly cationic am-
phipathic structure making them prone to interact with anionic
cell membrane surfaces.111,112 Some cationic amphipathic
peptides with anticancer activity are summarized in Table 3.
Much progress has been achieved in the structure-activity
relationship of anticancer peptides in recent decades, which
contributes both to an increased understanding of the immune
system and to their potential as clinical antibiotics. None-
theless, most studies on anticancer peptide are still in vitro.
More in vivo experiments of anticancer peptides are needed to
bridge across the clinical application.
CONCLUSIONS
The studies cited in this review indicated that biological
activities of peptides are closely associated with molecular
structure and molecular size. Peptides with higher ACE
inhibitory activity usually have aromatic or alkaline amino
acids in N-terminal, higher quantity of hydrophobic and
positively charged amino acids in C-terminal. Nonpolar
aliphatic peptides showed higher antioxidant activity. Both
primary and secondary structures are important to the anti-
cancer peptides. Due to the difficulty to isolate and purify
specific bioactive peptides from the mixture of natural
protein hydrolysates, the progress in structure-activity re-
search of bioactive peptides will play an important role in
synthesis of more specific, high bioactive, and low toxic
peptides for prevention and treatment of diseases such as
hypertension and different types of cancers. Currently,
products of bioactive peptide only take up a small market
place. With the urgent demand of human natural medicine,
research on active peptides will continue to advance.
AUTHOR DISCLOSURE STATEMENT
No competing financial interests exist.
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