Biomedicine & Pharmacotherapy 170 (2024) 116015

Contents lists available at ScienceDirect

Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Biomedical applications of synthetic peptides derived from venom of

animal origin: A systematic review
Jorge L. Díaz-Gómez a, Irene Martín-Estal a, Elizabeth Rivera-Aboytes b, Ramón Alonso Gaxiola-
Muñíz a, César A. Puente-Garza b, Silverio García-Lara b, Fabiola Castorena-Torres a, *
a
Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Ave. Morones Prieto 3000, Monterrey 64710, N.L., Mexico
b
Tecnologico de Monterrey, Escuela de Ingenieria y Ciencias, Ave. Eugenio Garza Sada 2501, Monterrey 64849, N.L., Mexico

A R T I C L E I N F O A B S T R A C T

Keywords: Development of therapeutic agents that have fewer adverse effects and have higher efficacy for diseases, such as
Synthetic peptide cancer, metabolic disorders, neurological diseases, infections, cardiovascular diseases, and respiratory diseases,
Bioactive are required. Recent studies have focused on identifying novel sources for pharmaceutical molecules to develop
Venom
therapies against these diseases. Among the sources for potentially new therapies, animal venom-derived mol­
Therapeutic peptide
ecules have generated much interest. Various animal venom-derived proteins and peptides have been isolated,
identified, synthesized, and tested to develop drugs. Venom-derived peptides have several biomedical properties,
such as proapoptotic, cell migration, and autophagy regulation activities in cancer cell models; induction of
vasodilation by nitric oxide and regulation of angiotensin II; modification of insulin response by controlling
calcium and potassium channels; regulation of pain receptor activity; modulation of immune cell activity;
alteration of motor neuron activity; degradation or inhibition of β-amyloid plaque formation; antibacterial,
antifungal, antiviral, and antiprotozoal activities; increase in sperm motility and potentiation of erectile function;
reduction of intraocular pressure; anticoagulation, fibrinolytic, and antithrombotic activities; etc. This systematic
review compiles these biomedical properties and potential biomedical applications of synthesized animal venom-
derived peptides reported in the latest research. In addition, the limitations and areas of opportunity in this
research field are discussed so that new studies can be developed based on the data presented.

1. Introduction various bioactivities in vitro and in vivo [3].

Chronic degenerative diseases pose a threat to global health, and
their prevalence and incidence have increased in recent decades. Dis­
eases can be classified into metabolic (diabetes and metabolic syn­
drome), neurological (Alzheimer’s disease [AD], Parkinson’s disease,
and other motor neuron diseases), cancer, cardiovascular (hyperten­
sion), and autoimmune diseases [1]. However, acute diseases, such as
infections, are a global health problem, particularly in third-world
countries [2]. New molecules from various natural sources have been
studied to develop novel treatments for these pathologies.
Animal venom from scorpions, snakes, vipers, wasps, bees, etc., are
potential therapeutic molecules. Many venoms comprise a mixture of
proteins and peptides, some of which have been identified and synthe­
sized. These venoms induce a wide range of physiological responses and
toxicities. Nevertheless, peptides derived from these venoms have been
studied for their potential therapeutic properties because they can have
This review aims to provide an update on the bioactive properties of
animal venom-derived synthetic peptides. The purpose was to present a
perspective on the potential use of venom-derived peptides in devel­
oping new therapeutic treatments for diseases.
2. Search methodology
The search methodology used in this systematic review was per­
formed in accordance with the guidelines of Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA) [4]. The search
was conducted using BiblioXplora, an exploration engine developed by
Tecnologico de Monterrey. The following databases were searched:
MEDLINE, Academic Search Ultimate, Academic Search Index, Com­
plementary Index, ScienceDirect, Gale Academic OneFile, Directory of
Open Access Journals, OAIster, Biomedical Index, Networked Digital
Library of Theses and Dissertations, OpenDissertations,

* Corresponding author.
E-mail address: fcastorena@tec.mx (F. Castorena-Torres).

https://doi.org/10.1016/j.biopha.2023.116015
Received 14 October 2023; Received in revised form 11 December 2023; Accepted 13 December 2023
Available online 19 December 2023
0753-3322/© 2024 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
J.L. Díaz-Gómez et al.
Journals@OVID, Supplemental Index, Springer Nature Journals, Gale In
Context: Opposing Viewpoints, NewsBank, SciELO, Business Source
Ultimate, Business Source Index, and JoVE Journal. The parameters for
the search were selected to identify original research articles in indexed
databases that reported the bioactivities or biomedical applications of
synthetic peptides derived from animal venom. The following search
parameters were used: ((venom [Abstract]) AND (peptide [Abstract])
AND (synthesis [Abstract])). A literature search was conducted by
limiting publication time from 2012 to 2022 (Fig. 1).
All duplicates in the initial search were eliminated automatically by
the search engine and not displayed in the initial results. The results
were analyzed manually to eliminate extra duplicates. Other criteria for
exclusion were: articles lacking full text, conference abstracts, thesis
dissertations, review articles, book chapters, poster sessions, magazine
articles, and news articles. Manual revision of scientific papers involved
an evaluation of their title, abstract, and content. Thus, only original
research papers published in indexed scientific journals that reported on
the bioactivity or biomedical applications of animal venom-derived
synthetic peptides (in vitro or in vivo) were considered. A further
manual selection of papers was made to precisely describe diverse bio­
activities (e.g., antibacterial, antiviral), because activities against mi­
croorganisms were considered “antimicrobial.” For the analytical
revision, only the general characteristics of the different methods were
described; for the purpose of this review, the analytical scope was not
the main approach.
Fig. 1. Flow diagram of literature search.
2
Biomedicine & Pharmacotherapy 170 (2024) 116015
The search methodology for this systematic review was according to
the guidelines of Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) 4. The search tool BiblioXplora from Tecno­
logico de Monterrey was used.
3. Sources of venom-derived peptides
Animal venom is characterized by a complex mixture of substances,
resulting in efficient and diverse biological effects with various molec­
ular targets and functions [5]. Although several animal venoms have
been reported in the literature, we refer to and focus on venoms with
significant biological effects. Animal venom is listed according to its
importance, prevalence, and occurrence.
Marine animal venoms, including peptide toxins from cones, snails,
and fish, represented > 25% of the reference studies. Some of the species
included are members of the genus Conus, including C. geographus,
C. achatinus, C. milneedwardsi, and C. purpurascens, as well as Clavus
davidgilmouri; snails, such as terebrid marine snails (e.g., Terebra varie­
gate) and the Brazilian fish Thalassophryne nattereri.
Scorpion venom accounted for approximately 20% of the cited re­
ports. Examples of the species in this category include Androctonus
australis, Buthus sindicus, Buthus martensii Karsch, Leiurus quinquestriatus,
Tityus serrulatus, Tityus stigmurus, and Urodacus yaschenkoi. Spider
venom ranked third, representing < 20% of the studies. Species included
Alopecosa marikovskyi, Chilobrachys jingzhao, Davus fasciatus, Lycosa
J.L. Díaz-Gómez et al. Biomedicine & Pharmacotherapy 170 (2024) 116015

singoriensis, Pelinobius muticus, and Phoneutria nigriventer.
Insect venom, specifically from the order Hymenoptera, represented
15% of the studies. Examples included the venom of Paravespula lewisii,
Polybia paulista, Polybia lewisii, Polybia dimorpha, and Vespula lewisii.
Snake venom was ranked last, with < 10% of the cited reports. Examples
of the species in this group are Daboia russelii, Deinagkistrodon acutus,
and Dendroaspis angusticeps.
Therefore, studies on new molecules from animal venom represent a
promising alternative that must be evaluated as new sources of novel
molecules with therapeutic potential for current and emerging diseases
[5].
4. Methods for the identification and synthesis of animal
venom-derived peptide
4.1. Separation, isolation, and purification
Recent studies have focused on the discovery and characterization of
biological components (peptides) from natural sources, such as animal
venoms, against different diseases, because most of these peptides have
numerous biological activities, such as anticancer activity [6].
Several techniques have been used to characterize, purify, and
isolate bioactive peptides from animal venoms, including liquid chro­
matography coupled with mass detection, reverse-phase chromatog­
raphy, acidified water, acidified acetonitrile, and linear gradients [6–8].
Differences in size and biochemical property between peptides deter­
mined the characteristics of the analytical method used for identifica­
tion, separation, and purification (Table 1). These parameters differ
between peptides; however, the basic principles of peptide separation
and purification remain unchanged.
These techniques have been used to identify bioactive peptides in
scorpions. Four fractions were obtained from Hemiscorpius lepturus
venom using 20 mM ammonium acetate [6]. Peptide size ranged from
11 to 75 kDa, with fraction 3 having the smallest peptide size. This
fraction was purified using liquid chromatography, and five peaks were
identified. All the peaks showed peptide sizes ranging from 11 to
17 kDa. The peptide was identified as leptulipin, which exhibits anti­
cancer activity.
Seven fractions were obtained from the venom of Buthus occitanus,
separated by size [7]. Fraction 3 was characterized by liquid chroma­
tography, and two proteins were identified: alpha-insect toxin Lqq3 and
alpha-like toxin Bom4 (7334.93 and 7287.96 kDa, respectively), which
exhibited anticancer activity.
Four fractions were obtained from the venom of A. australis and a
tetrapeptide was identified by UHPLC coupled to ESI-QTOF [8]. This
tetrapeptide was named A. australis tetrascopin-1 (AaTs-1), which had a
mass of 533.3158 m/z and antiproliferative activity.
4.2. Identification and sequence analysis of venom-derived peptides
Functional peptides from animal venom exhibit antiprotease prop­
erties [9]. Bioinformatics is extremely useful to identify and design small
bioactive molecules and examine their mechanisms of action [10].
Therefore, the analysis, sequencing, and isolation of animal venom-
derived peptides have become predominant techniques to obtain these
bioactive molecules.
Venom from the scorpion Chaerilus tricostatus, distributed only in
South Asia and southern Tibet, China, was cloned and functionally
identified. Reverse-phase high-performance liquid chromatography
(RP-HPLC) was used to determine the purity of the synthetic peptide.

Table 1
Summary of methods used to isolate, identify, and synthesize animal venom-derived bioactive peptides.
Peptide Peptide source Solvents used Column Activity Reference

Leptulipin Hemiscorpius lepturus ACN, water, C18 reverse-phase HPLC Anticancer activity against MCF-7 and HT-29 cancer cell 6
venom and TFA column lines
Buthus occitanus venom Buthus occitanus venom ACN, water, C18 reverse-phase HPLC Anticancer activity against HepG2 hepatocellular 7
peptides and TFA column carcinoma cell line in 3D cell culture
AaTs-1 Androctonus australis ACN, water, C18 reverse-phase HPLC Antiproliferative activity against MDA-MB-231 and MCF-7 8
venom and TFA column breast cancer cell lines
Conotoxins Conus achatinus venom ACN, water, Size exclusion column Targeting N-methyl-D-aspartic acid receptor 83
and TFA
Conotoxin protein Conus inscriptus venom ACN, TFA C18 reverse-phase HPLC Potential anticancer activity against cervical cancer cell 57
column lines
UAITx-Ate1 Actinia tenebrosa ACN, water, C18 reverse-phase HPLC Cytotoxicity against breast cancer 59
and TFA column
ShSPI Scolopendra hainanum Not specified C18 reverse-phase column Elastase inhibitor 9
venom
PE-BBI Pelophylax esculentus ACN, TFA C18 reverse-phase HPLC Serine proteinase inhibitor, potential treatment for cancer 14
secretion column
β-toxin Ceratogyrus darlingi ACN, water, C18 reverse-phase column Analgesic 73
venom and TFA
HL-7, HL-10 Hemiscorpius lepturus ACN, water, C18 reverse-phase HPLC Antimicrobial and hemolytic activities 46
venom and TFA column
μ-TRTX-Df1a Davus fasciatus ACN, water, C18 reverse-phase Modulatory activity 75
and TFA chromatography
AaeAP1, AaeAP2 Androctonus aeneas ACN, water, C18 reverse-phase HPLC Antimicrobial and anticancer activities 43
venom and TFA column
v-TRTX-Cc1a Pelinobius muticus ACN, water, C18 reversed-phase Inhibition of CaV channels 16
and TFA chromatography
Ctri9594 Chaerilus tricostatus ACN, water, C18 reversed-phase HPLC Inhibition against gram-positive bacteria 11
and TFA column
ShPI Scolopendra hainanum ACN, water, C18 reversed-phase HPLC Inhibitory effects on porcine pancreatic elastase and human 9
and TFA column neutrophils elastase
PE-BBI Pelophylax esculentus ACN, water, C5 reversed-phase HPLC Inhibition of trypsin activity, myotropic activity, and 14
and TFA column cytotoxicity in colorectal cancer cells
Wa Walterinnesia aegyptia ACN, water, C18 reversed-phase HPLC Profertility peptide and disulfide bridge connectivity 15
and TFA column
Tn CRT2-CRT3 Thalassophryne nattereri ACN, water, C18 Antimicrobial peptide 10
and TFA reversed-phase HPLC
column

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J.L. Díaz-Gómez et al.
The signal peptide sequence was analyzed using SignalP 5.0. The pep­
tide Ctri9594 precursor nucleotide sequence contained an open reading
frame with 69-amino acid (aa) residues, including a 21-aa signal pep­
tide, 14-aa mature peptide, 3-aa C-terminal post-transcriptional pro­
cessing signal, and 31-aa propeptide. It had inhibitory activity against
gram-positive bacteria, such as Bacillus thuringiensis, B. subtilis, Staphy­
lococcus aureus, and Micrococcus luteus [11].
Peptides from Scorpio maurus palmatus venom were evaluated with
RP-HPLC. The molecular weights of the peptides were confirmed by
mass spectrometry and sequence alignments were performed using
DNAMAN. A series of 14-residue fragments of Smp43, a 43-residue long-
chain non-cysteine-containing antimicrobial peptide (AMP) that is
nontoxic to mammalian cells and has antimicrobial activity against
gram-positive and gram-negative bacteria [12] was identified.
The Kazal-type serine protease inhibitor (ShSPI) was identified from
the cDNA library of venom from the glands of Scolopendra hainanum
through RNA extraction and cDNA synthesis, in addition to peptide
synthesis, refolding, protease analysis, and surface plasmon resonance
[9].
Snake venom metalloproteinase from Bothrops atrox venom provides
a basis for the identification of neutralizing epitopes on atroxilysin-I
(Atr-I) snake venom toxin and shows that the use of synthetic peptides
could improve the generation of immunotherapies. Atr-I was synthe­
sized using the core sequences of two epitopes spaced by two glycine
residues [13].
The mRNA sequence and primary structure of the Bowman-Birk
proteinase inhibitor (BBI)-type peptide, secreted from the skin of Pelo­
phylax esculentus, were identified using reverse transcription PCR and
liquid chromatography–mass spectrometry. The peptide showed anti­
cancer activity against human cancer cell lines DD-1, DKS8, HCT116,
and HKE3 [14].
Venom from the Egyptian black egg snake Walterinnesia aegyptia was
identified using RP-HPLC and cation exchange chromatography and
sequenced de novo using a combination of matrix-assisted laser
desorption ionization time-of-flight mass spectrometry (MALDI-TOF/
TOF-MS/MS) and liquid chromatography electrospray ionization
quadrupole TOF-MS. Walterospermin was obtained as 57-aa residue
peptide, with three disulfide bridges, and a new toxin of 6389.89 Da
[15].
Seven active AMPs obtained from the toadfish T. nattereri, homolo­
gous to the cocaine- and amphetamine-regulated transcript peptides,
were identified by MALDI-TOF/MS using an Ettan MALDI/TOF/Pro
system mass spectrometer. Edman degradation was performed using a
Shimadzu PPSQ-21 automated protein sequencer to determine the pri­
mary amino acid sequence. TnCRT2 and TnCRT3 showed 50% and 40%
hemolysis, respectively, suggesting that the mechanism of action in­
volves membrane disruption [10].
RP-HPLC is the most common method for identifying venom. RP-
HPLC separates the molecules by their hydrophobicity, identifies
venom composition, and determines the methods to manipulate the
peptide. Generally, sequence analysis is performed using MALDI-TOF/
TOF MS/MS, which is a fast and accurate method. These techniques
are standard and can easily be adapted for peptides.
4.3. Peptide synthesis methodologies
The most effective peptide synthesis method is determined by the
characteristics of venom peptides [16]. The most relevant methods
include chemical synthesis through stepwise solid-phase synthesis using
the Fmoc method and native chemical ligation [17,18].
Snake venom is a complex chemical mixture of pharmacologically
active compounds, such as enzymes, peptides, and proteins, and non-
protein components, such as carbohydrates, lipids, and metal ions
[15]. The 57-residue polypeptide mambalagin from snake venom was
synthesized by a combination of solid-phase peptide synthesis and
native chemical ligation [18]. The same combination of techniques
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Biomedicine & Pharmacotherapy 170 (2024) 116015
showed favorable results for W. aegyptia walterospermin [15]. Chemical
ligation techniques are increasingly employed to synthesize
> 50-residue peptides [19]. Native chemical ligation was used to syn­
thesize difficult venom peptide sequences [16]. By contrast, two venom
peptides (lebetin 1 and 2) of Vipera lebetina were chemically produced
using the solid-phase method [20]. Furthermore, anoplin, a peptide of
10-aa residues from the spider wasp Anoplius samariensis, was produced
using the same technique [17].
Scorpion venom is a rich source of bioactive peptides. Liocheles
australasiae venom peptides were chemically synthesized manually
using Fmoc-based solid-phase peptide synthesis to examine the struc­
tural factors with insecticidal and antimicrobial activities [19]. Five
analogs of a natural peptide from B. martensii were synthesized using the
same technique and their antimicrobial and hemolytic activities were
compared [21]. For ligation, a Cys residue is essential, similar to that for
scorpion peptides [19]. The solid-phase method can be developed using
an automatic synthesizer to streamline the process and analyze more
samples [20]. Manual solid-phase peptide synthesis is an alternative
method [21].
Spider venom is a rich source of biologically active substances that
selectively target physiological processes in insects and mammals.
Although some techniques are used more successfully for peptides with
certain characteristics, they can be used for a wide variety of peptides,
such as the 39-residue peptide of the tarantula P. muticus (previously
Citharischius crawshayi), for which a combination of Boc solid-phase and
native chemical ligation was used [16].
The main components of cone snail venom are conotoxins, small
(10–40 residues), and highly constrained peptides (2–4 disulfide
bridges), which can be synthesized using Fmoc-based solid-phase syn­
thesis [22]. The properties of the venom must be known for successful
peptide synthesis, and the best method must be selected based on the
amino acid sequence.
5. Bioactivities of venom-derived synthetic peptides
5.1. Anticancer effect
Cancer is a life-threatening illness, and despite advances in tradi­
tional approaches, such as surgery, chemotherapy, and radiotherapy,
adequate care remains a challenge. Owing to the enormous benefits
derived from the host immune response, immunotherapy is considered
one of the most effective methods against cancer, because it induces host
immune function, destroying malignant cells, rather than specifically
targeting cancerous cells.
Structural similarities of peptides with protein molecules endow
them with a remarkable ability to resolve such issues by either specif­
ically inducing the immune response or enhancing therapeutic effects.
Peptide-based substances have great potential as immunotherapeutic
agents for treating several types of cancers, e.g., lung, colorectal, breast,
pancreatic, prostate, and gastric, from early diagnosis [23]. These pep­
tides, also known as therapeutic peptides, have numerous advantages
over antibodies owing to their smaller size, easier synthesis, and ability
to penetrate the cell membrane. Their roles in cancer include the
transport of radionuclides, cytotoxic drugs, hormones, and vaccines.
Thus, cancer immunotherapy is a promising strategy for cancer treat­
ment because it can prevent tumor recurrence and metastasis. It pro­
duces long-term memory and triggers immunological responses against
localized cancer cells [23].
Animal venom is a major source of bioactive peptides, most with
anticancer functions (Fig. 2).
5.1.1. Amphibian venom
Amphibian venom-derived peptides have great potential in anti­
cancer drug discovery. For example, a BBI-type peptide (named PE-BBI),
isolated from the skin secretions of P. esculentus, showed anticancer
activity against several human colorectal cancer cell lines, because it
J.L. Díaz-Gómez et al. Biomedicine & Pharmacotherapy 170 (2024) 116015

Fig. 2. Potential therapeutic properties of animal venom-derived peptides in cancer. Several types of venom peptides obtained from animals are considered potent
antitumor strategies due to their inhibition of cell proliferation and motility. For example, scolopin-2, mastoparan, mitP, and ZXR-1 dissipate mitochondrial
membrane potential (MMP), producing cytochrome c release and apoptosis. Cltx inhibits voltage-gated Cl− channels, hindering cell migration and promoting
neurotoxicity. Melittin and gonearrestide arrest the cell cycle in the G1 phase. LZ1 can stimulate AMPK-dependent autophagy. Polybia-CP, VmCT-1, LVTX-8, and
LVTX-9 produce electrostatic interactions that result in peptide internalization and apoptosis. Melittin, CM11, Dec-NH2, ZXR-2, AaeAP, AaeAP2, checacin 1, and Cu-
1a disturb membrane integrity and cause membrane pore formation, leading to cell lysis. Tv1 and soricidin can overexpress transient receptor potential (TRP)
channels, resulting in an increase in Ca2+ intracellular levels, and thus, apoptosis. Cltx: chlorotoxin; Cu-1a: cupiennin-1a; mitP: mitoparan; MMP: mitochondrial
membrane potential; TRP: transient receptor potential channels; Tv1: terebrid snail venom peptide.

suppressed the release of tumor-promoting factors, such as superoxide
anion radicals and hydrogen peroxide. It can also inhibit proteolytic
processes involved in carcinogenesis [14].
5.1.2. Centipede venom
Scolopin-2, a novel cationic peptide obtained from centipede venom,
exhibits anticancer effects. Several scolopin-2 analogs have been tested.
Scolopin-2-NH2 was found to have more effective antitumor activity.
Both peptides triggered the intrinsic apoptotic pathway in HeLa cells,
reducing cell viability in a dose-dependent manner [24].
5.1.3. Bee and wasp venom
Melittin, a cationic peptide toxin found in bee venom (Apis mellifera),
is effective against cancer cells (e.g., HeLa cells) as well as ovarian and
gastric cancers, because it can prevent tumor cell metastasis by mini­
mizing motility [25]. This peptide inhibits phosphorylation of the
AKT/mTOR/S6K1/4E-BP1 signaling pathway and suppresses cell pro­
liferation, leading to arrest in the sub-G1 phase of the cell cycle. In
addition, it downregulates cyclin D1 and cyclooxygenase-2 (COX-2)
expression, inducing apoptosis and loss of mitochondrial membrane
potential [26]. In mouse models and preclinical cell cultures, melittin
can bind to negatively charged membrane surfaces and disturb the
integrity of phospholipid bilayers. Melittin forms α-helices that aggre­
gate on the membrane to form pores, causing leakage of ions and mol­
ecules and promoting cell permeability and lysis [27]. Pore formation is
a result of melittin dimerization. The pore structure allows melittin to
cross the cytoplasmic barrier and enter the nucleus, involving several
endocytic receptors, such as neurophilin 1, low-density lip­
oprotein-related protein receptor 1, and transferrin receptor [25].
Therefore, the conjugation of melittin with hormone receptors and
gene therapy using melittin is applicable as novel therapy for treating
prostate and breast cancers [25].
Cecropin and melittin are the two most widely studied cationic
AMPs. CM11 is a hybrid cecropin–melittin peptide that includes an 11-
residue sequence with an –NH2 group derived from residues 2–8 of
cecropin A and residues 6–9 of melittin, which were designed and pro­
duced to improve the properties of the original peptides. CM11 is a
chimeric peptide derived from bee venom and butterfly compounds. The
high rate of late apoptosis after exposure to CM11 revealed that this
peptide can disrupt membrane integrity [28]. Several in vitro studies
have shown that CM11 has higher cytotoxicity in LNCAP (human
prostate cancer tissue) and SP2/0 (mouse spleen tissue) cell lines,
indicating that it could be effective against prostate cancer; however,
further studies are needed [29].
The peptide polybia-MPII was discovered in the venom of P. paulista.
Polybia-MPII showed cytotoxicity against mouse embryonic fibroblast
cells NIH 3T3 [30]. The synthetic peptide analog polybia-CP venom
from P. paulista is relevant for targeting cancer cells because of its hel­
icity, net charge, hydrophobic properties, and derivatives that are
important for peptide–membrane interactions. This peptide has
increased activity against epithelial-like cancer cells (MCF-7 and
SK-Mel) compared with neuroblastoma and hepatocyte cells, principally
due to heterogeneous morphological and physiological characteristics.
Owing to its nature, this peptide promotes electrostatic interactions with
cancer cell membranes, which leads to its cellular internalization,
resulting in apoptosis [31].
Arthropod venom is a rich source of biologically active compounds.
For example, AMPs have been isolated and characterized from wild bee
venom reservoirs. The peptides (e.g., melectin, lasioglossins, halictines,
and macropin) and their analogs display cytotoxicity toward three

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J.L. Díaz-Gómez et al.
cancer cell lines: HeLa S3, CRC SW 480, and CCRF-CEM T, suggesting
the use of medically applicable drugs based on AMPs [32]. Decoralin
(Dec-NH2), an α-helical natural AMP derived from Oreumenes decoratus
wasp venom, and its synthetic variants generated through peptide
design, alters the ultrastructure of the cancer cell membrane, leading to
necrotic death in MCF-7 breast cancer cells [33].
Biologically active cell-penetrating peptides (CPPs) constitute an
emerging class of therapeutic agents found in wasp venom. Mastoparan
is a CPP that modulates mitochondrial activity and triggers caspase-
dependent apoptosis in cancer cells. Its analog, mitoparan (mitP), ex­
hibits enhanced cellular penetration. MitP dissipates mitochondrial
membrane potential and promotes cytochrome c release, resulting in
tumor cell apoptosis [34].
5.1.4. Scorpion venom
BmKn-2, a peptide isolated from the venom of the scorpion Meso­
buthus martensii Karsch, consists of a basic, α-helical peptide with an
amidated C-terminal cationic peptide. It can inhibit the growth and
proliferation of several cancer cell types, including oral and colon can­
cers, through its action on signaling intermediates that promote
apoptosis. Thus, BmKn-2 could function as a chemotherapeutic agent
against human oral cancer as a novel therapeutic strategy for developing
cationic antimicrobial and anticancer peptides [35,36].
VmCT1 is an α-helical AMP obtained from the venom of Vaejovis
mexicanus smithi. In vitro studies assessing the anticancer activity of
VmCT1 against MCF-7 mammary cancer cells have shown that single
substitutions in the peptide chain led to different physicochemical fea­
tures, in addition to selectivity toward cancer cells and disturbance of
cancer cell membranes. Owing to its cationic net charge, this peptide can
be attracted to cancer cell membranes by electrostatic interactions,
resulting in membrane penetration or destabilization. The physico­
chemical parameters of peptides, such as net charge, hydrophobicity,
and helicity, play important roles in the selectivity and activity of
α-helical anticancer peptides [37].
Chlorotoxin (Cltx), a peptide isolated from the venom of
L. quinquestriatus, has four disulfide bonds containing a β-sheet and a
helical structure. This peptide has antiangiogenic activity and inhibits
cell migration through voltage-gated chloride channels, causing neuro­
toxicity [38]. Neuropilin-1 (NRP1), an endocytic receptor on tumors and
endothelial cells, was identified as a novel Cltx target. Binding of NRP1
by Cltx increased drug uptake into tumors, enhancing antitumor activity
in vivo. Studies on the anti-apoptotic protein Bcl-xL have shown how
deamidation can influence its function in apoptosis and autophagy, and
thus, its oncogenic properties. These findings should facilitate tumor
selection for Cltx-based therapeutics and diagnostics [39].
The 48-aa residue peptide mauriporin belongs to the group of scor­
pion non-disulfide-bridged peptides. Mauriporin is a cationic α-helical
peptide obtained from the cDNA of the Moroccan scorpion Androctonus
mauritanicus venom. Mauriporin exhibits potent anticancer activity,
confirming the multifunctional nature of this peptide class. It signifi­
cantly inhibited the proliferation of three prostate cancer cell lines.
Mauriporin displayed selective antiproliferative and membrane-lytic
activities against cancer cells and diminished hemolytic activity
against mammalian erythrocytes in the concentration range required to
promote cancer cell death [40].
A novel anticancer peptide, ZXR-1, derived from mauriporin, was
developed. Lytic peptides have several advantages over traditional
drugs, including low drug resistance and xenobiotic toxicity. ZXR-1
peptide showed potent cytotoxicity in several cancer cell lines and
induced apoptosis. A mutation, named ZXR-2, was introduced by
changing lysine 14 to leucine. The anticancer activity of ZXR-2
improved up to 10-fold, and ZXR-2 adopted cell lysis as its mode of
action. ZXR-1 is internalized into cells by endocytosis, targets mito­
chondria, and induces cell apoptosis, whereas ZXR-2 causes membrane
lysis. These results suggest that even slight differences in peptide
structure can have a great impact on the mechanism of its action [41].
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Biomedicine & Pharmacotherapy 170 (2024) 116015
Scorpion toxins active on Ca2+ channels are members of the scor­
pionic calcine family, which consists of basic peptides with 33-aa resi­
dues stabilized by three disulfide bonds and an “inhibitor cystine-knot.”
The first Ca2+ channel toxin identified in T. serrulatus (Ts) venom was a
CPP named CPP-Ts. The nuclear internalization of CPP-Ts was observed
in cancer cell lines, but not in normal cells, suggesting that CPP-Ts is a
promising tool for the delivery of antitumor drugs, given its nuclear
sensitivity to drug-induced DNA damage and lack of specificity of
available drugs. Such a specific nuclear drug delivery tool may increase
the therapeutic efficacy and minimize the side effects of cancer therapy.
CPP-Ts reached the nucleus the fastest, indicating high nuclear speci­
ficity [42].
AaeAP1 and AaeAP2 (Aae: Androctonus aeneas; AP: AMP) are novel
peptides obtained from the venom of the scorpion A. aeneas. Their
respective peptide analogs with improved cationicity and amphipa­
thicity showed antiproliferative activity against human cancer cell lines,
with both causing > 85% inhibition of cell proliferation and acting
predominantly by cancer cell membrane lysis. Synthetic replicates of
these peptides displayed antimicrobial activity against the gram-positive
bacterium S. aureus and the yeast Candida albicans, but were ineffective
against the gram-negative bacterium Escherichia coli [43].
Checacin1, a linear cationic peptide obtained from the pseudoscor­
pion Chelifer cancroides, exhibits several cytotoxic activities. It exerts its
toxic effects by binding to cell membranes and causing pore formation,
leading to apoptosis and cell death [44].
Scorpion toxins have been proposed as promising alternatives for
targeted glioblastoma therapy and diagnosis. A. australis tetrascorpin-1
(AaTs-1), the first tetrapeptide found in A. australis scorpion venom
(Aa) and an agonist of the G-coupled formyl peptide receptor, is
involved in glioma cell proliferation and exhibits an antiproliferative
effect against human glioblastoma cells. AaTs-1 enhances the expression
of p53 and inhibits ERK, p38, and JNK phosphorylation. AaTs-1 may
improve glioblastoma therapy and overlay the design of analogs with
improved activity and affinity [8,45].
H. lepturus (family Scorpionidae, subfamily Hemiscorpiidae) is the
most toxic scorpion species, contributing to ~95% of scorpion sting
mortalities. Scorpion venom from this species was fractionated by RP-
HPLC, and two peptide fractions were identified by tandem mass spec­
trometry: HL-10 and HL-7, both of which were cytotoxic to A549 cells,
without hemolytic effect. They could adopt flexible and amphipathic
α-helix structures when placed in the cell membrane, with the HL-7
peptide having a higher antioxidant potency. Thus, HL-10 and HL-7
peptides are potential candidates for drug design [46].
Gonearrestide, a scorpion venom-derived peptide, is a highly potent
anticancer peptide that acts on human cancer cells without causing
cytotoxic effects on epithelial cells and erythrocytes. Studies have shown
that this peptide can inhibit the growth of primary colon cancer cells and
solid tumors by triggering cell cycle arrest in the G1 phase through the
inhibition of cyclin-dependent kinase 4 (CDK4) and upregulating the
expression of cell cycle regulators/inhibitors, such as D3, p27, and p21.
In an in vivo xenograft mouse model, gonearrestide reduced the volume
of implanted tumors in a dose-dependent manner. Thus, gonearrestide is
a potential therapeutic agent because it exerts its anticancer activity in
vivo [47].
5.1.5. Snake venom
Snake venom phospholipases (PLA2s) are valuable scaffolds for
developing short peptides that target parasites, bacteria, and cancer
cells. In vitro studies have shown the cytotoxic activities of three bio­
mimetic peptides (pCergo, pBmTxJ, and pBmje), demonstrating their
therapeutic potential [48]. These proteins can remodel membrane ele­
ments specifically through their C-terminal regions, which are typically
recognized by a high density of cationic and hydrophobic amino acids
[48].
LZ1, a peptide derived from the venom of Bungarus fasciatus, signif­
icantly inhibits the growth of pancreatic cancer cells by inducing
J.L. Díaz-Gómez et al.
autophagy-dependent cell death in vitro and in vivo. LZ1 targets cell
surface nucleolin to induce AMPK-activated autophagy-dependent
death in pancreatic cancer cells. Therefore, targeting the autophagy–LZ1
axis is a promising strategy for developing therapeutic agents against
pancreatic cancer [49].
5.1.6. Spider venom
LVTX-8, obtained from the spider Lycosa vittate, is an amphipathic,
alpha-helical, CPP with anticancer activity. It promotes apoptosis and
inhibits the proliferation and migration of lung cancer cells in vitro and
in vivo. CPPs are a class of peptides with 5–30 aa that penetrate the cell
membrane and enter cells through endocytosis and direct translocation.
LVTX-8 peptide is an α-helix CPP that penetrates cells to promote cell
death, through its regulation of p53 and cadherin-related gene expres­
sion. Therefore, LVTX-8 is a potential drug for targeting lung cancer
progression, as demonstrated in A549 xenograft nude mice treated with
this peptide. In this study, LVTX-8 treatment inhibited xenograft tumors
and increased the number of apoptotic cells (detected by the TUNEL
assay) [50].
Additionally, L. vittata venom contains LVTX-9, a novel peptide that
exhibits characteristics of APCs, such as linear nature, α-helix confor­
mation, amphipathicity, and in vivo and in vitro anticancer properties.
Nevertheless, it has lower cytotoxicity than other APCs, such as LVTX-8
and melittin. Octadecanoic acid modification of LVTX-9 produced
LVTX-9-C18, which had strong membrane-lytic activity and induced cell
membrane disruption in cancer cells [51].
The peptide cupiennin-1a (Cu-1a) is present in the venom of
Cupiennius salei and belongs to a group of peptides called cupiennins. Cu-
1a contains a cationic α-helical structure that disrupts cytoplasmic
membranes through osmotic shock, leading to cell lysis. Cu-1a demon­
strated high cytotoxicity against mammalian cells; therefore, a study
designed seven analogs of Cu-1a: R1a, R1b, R2b, R3b, R6b, R8b, and
R10b, based on its primary structure. All peptides exhibited antitumor
activity against breast adenocarcinoma lines, displaying a stronger ef­
fect against MCF-7 and MDA-MB-231 cell lines. In addition, Cu-1a was
active against different human leukemia cell lines [52].
Latarcin-3a, a peptide derived from Lachesana tarabaevi toxin, has
several antimicrobial activities. Numerous synthetic peptide analogs of
latarcin-3a were generated. Lt-MAP3 had the best antibacterial activity,
and Lt-MAP2 had the best antitumor activity. Promiscuous AMPs have
been excellent candidates for developing alternative bioactive com­
pounds that combat and control bacteria and tumor cell lines, proving
that the rational design of multifunctional AMPs may be a promising
alternative for treating emerging diseases, such as bacterial infections
and tumor cells [53].
LyeTxI-b is a synthetic peptide derived from Lycosa erythrognatha
venom that showed antibiotic activity in a 4T1 mouse mammary car­
cinoma model. LyeTxI-b reduced tumor growth and lung metastasis,
with no signs of toxicity in healthy or cancerous mice. LyeTxI-b acted as
an efficient regulator of the 4T1 tumor microenvironment by modu­
lating several cytokines, such as TGF-β, TNF-α, IL-1β, IL-6, and IL-10, in
the primary tumor and the lung, spleen, and brain. In a 4T1 mouse
mammary carcinoma model, LyeTxI-b induced apoptosis and inhibited
cell proliferation. Thus, cationic AMPs are a potential immunomodula­
tory target for developing therapies against breast cancer and improving
clinical outcomes [54]. In an in vitro model of colorectal cancer (chicken
chorioallantoic membrane model for tumor development), LyeTxI-b
exhibited antitumoral and antiangiogenic activities. It reduced tumor
area without promoting an inflammatory reaction, suggesting its role as
a new anticancer drug for colorectal carcinoma. LyeTxI-b could reduce
blood vessels, similar to bevacizumab, an antiangiogenic monoclonal
antibody used against colorectal cancer [55].
Agatoxin (AgTx), a peptide isolated from spider venom, contains a
cysteine knot motif known as knottins and has emerged as a promising
agent for noninvasive molecular imaging of tumors in living objects.
Knottins share a common disulfide-bonded framework and contain
7
Biomedicine & Pharmacotherapy 170 (2024) 116015
loops of variable lengths and compositions that are constrained to the
core of the antiparallel β-strands. These cells exhibit rapid tumor
localization and blood clearance through the kidneys, resulting in robust
tumor contrast compared with the surrounding tissue. AgTx was first
used as a molecular scaffold for protein engineering and in vivo imaging.
AgTx, an ion channel inhibitor, can be used as a platform for con­
structing peptides that bind with high affinity to clinically relevant
integrin receptors. Cell-binding assays performed on K562 leukemia
cells demonstrated that AgTx could be engineered to bind with high
affinity to a tumor-associated receptor target [56].
5.1.7. Marine snail venom
Marine snails, such as Conus inscriptus, are abundant sources of bio­
logically important conopeptides, with potential applications in drug
development. Conopeptides exhibited cytotoxicity against HeLa-HPV
16-associated cell lines and brine shrimp, proving that they could be
used as anticancer agents [57].
Terebrid snail venom peptide (Tv1), a venom peptide from the
predatory marine snail Turritella variegata, shows specific and selective
cytotoxicity in murine liver cancer cells, where it binds the tumor cell
membrane and modulates TRPC6 or vallinoid type 6 (TRPV6) ion
channels. Owing to its selectivity and mechanism of action, Tv1 has been
used to treat hepatocellular carcinoma—the most common type of liver
cancer. Tv1 inhibited the proliferation of murine hepatocellular carci­
noma cells and significantly reduced tumor size in Tv1-treated synge­
neic tumor-bearing mice. Tv1 binds overexpressed transient receptor
potential (TRP) channels, which leads to the downregulation of COX-2
and PGE2 function, resulting in calcium-dependent apoptosis. Thus,
Tv1 minimizes the growth of hepatocellular carcinoma cells [58].
5.1.8. Sea anemone venom
Sea anemone venom is a rich source of peptides with interesting
pharmacological and structural properties. A novel 13-aa residue pep­
tide has been identified in Actinia tenebrosa, called U-AITx-Ate1. This
peptide contains a single disulfide bridge and bears no significant ho­
mology to other peptides from sea anemones or other species. U-AITx-
Ate1 showed moderate cytotoxicity against the breast cancer cell lines,
MCF-7 and MDA-MB-231. U-AITx-Ate1 is believed to be used by
A. tenebrosa in prey capture and defense against predators [59].
5.1.9. Soricide venom
Soricidin, a 54-aa peptide found in the paralytic venom of the
northern short-tailed shrew Blarina brevicauda, inhibits the transient
receptor potential of TRPV6 calcium channels. TRPV6 channel expres­
sion is upregulated in numerous primary and metastatic carcinomas.
Because siRNA-mediated silencing of TRPV6 increased apoptosis and
reduced proliferation, the channel has gained much attention as a
therapeutic target. Both SOR-C13 and SOR-C27 inhibited calcium influx
in TRPV6 overexpressing cells and were more effective at reducing cell
viability. SOR-C27 reduced the size of SKOV-3 xenograft tumors in vivo,
which was comparable with the aggressive treatment used for ovarian
cancer [60].
5.2. Cardiopulmonary protection
5.2.1. Antihypertensive agent
Myocardial infarction is one of the most frequent causes of heart
failure (HF). Myocardial infarction is attributed to decreased or total
cessation of blood flow to the myocardium, leading to ventricular
remodeling—a process that causes several structural lesions in the tissue
[61].
Percutaneous intervention is the reference therapy for acute
myocardial infarction. It restores blood flow to the ischemic myocar­
dium and prevents the consequences of ischemia-reperfusion. Natri­
uretic peptides (NPs) are crucial therapeutic tools for HF because of their
vasodilating, natriuretic, and diuretic actions. For example, B-type NP
J.L. Díaz-Gómez et al. Biomedicine & Pharmacotherapy 170 (2024) 116015

(BNP), which is secreted from the ventricles to reduce ventricular
fibrosis, is considered an essential tool in HF therapy [61]. Animal
venom has become an important source of these peptides, which can
used as therapeutic tools for numerous diseases, such as HF [62]. Their
mechanisms of action is shown in Fig. 3.
Snake venom-derived compounds, such as NP from Dendroaspis, are
the most promising therapeutic options for HF because of their high
stability and potency. For example, lebetin 2 (L2), a snake venom-
derived BNP isolated from Macrovipera lebetina venom, attenuates the
adverse effects of HF. In murine models, a single injection of L2 prior to
reperfusion (as opposed to BNP treatment) can diminish fibrosis, ne­
crosis, and inflammatory cell recruitment, promoting endothelial cell
regeneration caused by the activation of the NP receptor (NPR)/cyclic
guanosine monophosphate (cGMP) signaling pathway. Thus, L2 treat­
ment increased coronary blood flow [61].
Several compounds in snake venom alter the
renin–angiotensin–aldosterone system, including bradykinin-
potentiating peptides (BPPs), also known as proline-rich oligopeptides
(PROs). BPPs inhibit angiotensin-converting enzyme, thus decreasing
angiotensin II synthesis and promoting vasodilation and hypotension,
leading to toxin diffusion, which is characteristic of hypotensive shock
due to envenomation [63,64]. In vivo rat model studies have corrobo­
rated that PROs and BPPs have hypotensive effects similar to those
observed in Bitis spp. envenomation [63]. This suggests that PROs and
BPPs can be used to develop drugs against hypertension, such as
LmrBBP9, isolated from Lachesis muta rhombeata venom, which reduces
blood pressure in rat experimental models [64].
Hypotensins (TsHpt-I and TsHpt-II), which are linear peptides in
T. serrulatus venom, have proinflammatory effects that increase macro­
phage infiltration and IL-6 and TNF production in murine models. Thus,
the release of both inflammatory cytokines can promote vasodilation
and, on a large scale, lead to shock, a characteristic consequence of
hypotension due to envenomation [62].
Notably, HF dysfunction can lead to acute kidney injury. This pa­
thology is characterized by a reduction in renal function and an increase
in blood pressure and vascular resistance, among other physiological
changes. One possible therapy is to simulate brain NP activity. These
molecules act as vasodilators and natriuretics in the body by stimulating
NO production [65]. NPCd, derived from the NP2_Casca peptide isolated
from Crotalus durissus cascavella venom, has important cardiovascular
regulatory activities. NPCd increased renal function parameters, such as
glomerular filtration rate, filtration fraction, and fractional Na+, in rats
with kidney injury. NPCd increased NO production and reduced NADPH
activity in the aorta. Thus, NPCd exerts hypotensive and
cardiorenal-protective effects through the NO and MAPK pathways.
Thus, it appears that NPCd exerts its effects through NP receptor C [65].
Another important pathology related to developing hypertension is
cardiorenal syndrome, such as chronic kidney disease. NPCd reduced
median arterial pressure in nephrectomized rats, potentiated the anti­
hypertensive effects of enalapril in nephrectomized rats, and decreased
the serum levels of NADPH and reactive oxygen species (ROS) in treated
rats [66]. NPCd competitively inhibits neprilysin, an enzyme that de­
grades NPs (ANP, BNP, and CNP) and an important physiological
regulator of blood pressure, and reduces its levels through vasodilation.

Fig. 3. Potential antihypertensive mechanisms produced by snake venom peptides. NRPA and NRPB activation (dotted line) by snake venom peptides, such as L2,
BPPs, LmrBP9, TsHpt-I and II, HL-7, and HL-10, produces cGMP and activates PKG, a protein kinase that phosphorylates PLN, an integral membrane protein that
regulates SERCA (Ca2+ ATPase). This phosphorylation induces Ca2+ uptake into the endoplasmic reticulum, resulting in vasodilation. Snake venom peptides inhibit
ACE, decreasing AngII synthesis and increasing IL-6 and TNF production, enhancing vasodilation, hypotension, toxin diffusion, and the characteristic shock asso­
ciated with envenomation. By contrast, NPCd snake venom peptide can bind to NRPC (dashed line), promoting PLC activation and NO production by eNOS, which
activates GC to produce cGMP, leading to vasodilation. NO can decrease ROS, NADP in the aorta, and RAAS, and increase renal parameters, such as glomerular
filtration rate, filtration fraction, and fractional Na+ . AC: adenylyl cyclase; ACE: angiotensin-converting enzyme; AngII: angiotensin II; BPPs: bradykinin-potentiating
peptides; CAT: catalase; cGMP: cyclic guanosine monophosphate; DAG: diacylglycerol; eNOS: endothelial nitric oxide synthase; ER: endoplasmic reticulum; GTP:
guanosine triphosphate; IL-6: interleukin 6; IP3: inositol triphosphate; IP3R: inositol triphosphate receptor; L2: lebetin 2; MDA: malondialdehyde; NADPH: nico­
tinamide adenine dinucleotide phosphate; NO: nitric oxide; NPRA: natriuretic protein receptor A; NPRB: natriuretic protein receptor B; NPRC: natriuretic protein
receptor C; PKG: protein kinase G; PLC: phospholipase C; PIP2: phosphatidylinositol diphosphate; PLN: Fosfolamban; RAAS: renin-angiotensin–aldosterone system;
ROS: reactive oxygen species; SOD: superoxide dismutase; TNF: tumor necrosis factor; TsHpt-I and II: hypotensins.

8
J.L. Díaz-Gómez et al.
This effect, in addition to the inhibition of the
renin–angiotensin–aldosterone system by enalapril, causes vaso­
relaxation, which decreases mean arterial pressure. The combined
antioxidant effects of NPCd and enalapril could contribute to a decrease
in blood pressure.
An O-glycosylated peptide obtained from the venom of the Austra­
lian snake Tropidechis carinatus, called TcNPa, shows vasodilatory ac­
tivity, by activating both natriuretic protein receptor A (NPR-A) and B
(NPR-B). The novelty of this peptide lies in its glycosylation and ɑ-he­
lical structure, compared with the sheet secondary structures of NPs.
However, the pharmacological importance of these physicochemical
characteristics is yet to be determined [67].
Treatment with the antihypertensive peptides, HL-7 and HL-10,
lowered systolic and diastolic blood pressure, and therefore, mean
arterial pressure in induced hypertensive rats. The main mechanism of
their bioactivity relies on the inhibition of angiotensin-converting
enzyme; however, this has not been proven in vivo. Additionally, both
peptides demonstrated antioxidant activity by reducing malondialde­
hyde levels and increasing the concentrations of antioxidant enzymes,
such as catalase and superoxide dismutase [68].
Several preventive and therapeutic effects have been reported for
venom-derived peptides in cardiovascular disease. This suggests that
they are important candidates for developing antihypertensive and
cardiovascular modulators. Data from in vivo and clinical studies are
required to determine the potential of these peptides as drug candidates
for treating cardiovascular diseases.
5.2.2. Regulation of pulmonary activity
Elastases are an important group of serine proteases involved in
extracellular matrix degradation and elastin cleavage. Human neutro­
phil elastase, released during degranulation, is involved in inflammatory
and immune responses. Deregulation of elastase activity can lead to
several diseases, particularly in the respiratory tract. Therefore, elastase
inhibitors have been postulated as excellent candidates for treating lung
diseases. For example, sivelestat, a human neutrophil elastase inhibitor,
is used in acute lung injury and pulmonary fibrosis [9].
Numerous elastase inhibitors have been discovered in animal venom.
For example, SPI in the venom of S. hainanum, named ShSPI, has better
inhibitory effects on porcine pancreatic elastase and human neutrophil
elastase than sivelestat. This demonstrates animal venom-derived pep­
tides as potential candidates for developing new drugs against diseases
affecting various organ systems in humans [9].
5.3. Endocrine regulation
5.3.1. Antidiabetic
Diabetes is a chronic, metabolic, long-term disease characterized by
elevated blood glucose levels. Its prevalence is increasing owing to the
increase in obesity and insulin resistance. Approximately 500 million
people have diabetes, and this number is expected to increase by ~25%
by 2030 [69].
Diabetes has several adverse consequences, such as hyperglycemia,
kidney disease, nervous system and eye damage, and cardiovascular
events (e.g., coronary heart disease, stroke, and peripheral and micro­
vascular diseases) [69]. Therefore, identifying new treatments to miti­
gate acute and long-term alterations could alleviate healthcare costs for
both individuals and governments.
The most common treatments for diabetes include biguanides (e.g.,
metformin), sulfonylureas (e.g., tolbutamide and glibenclamide) [69],
inhibitors of dipeptidylpeptidase 4 (iDPP4), and sodium-glucose
cotransporter-2 (SGLT-2) [70]. Other treatments stimulate insulin
secretion (meglitinide analogs) or sensitivity (thiazolidinediones).
However, their use is under consideration because they have hypogly­
cemic effects or cause cardiovascular events [69]. Efforts are being made
to develop new treatments to restore insulin sensitivity and secretion.
The discovery of animal venom-derived peptides has opened the
9
Biomedicine & Pharmacotherapy 170 (2024) 116015
door for developing new therapies against diabetes, and their mecha­
nisms of action are represented in Fig. 4. Exendin-4 (also called exena­
tide) was one of the first peptides identified in the venom of the
poisonous lizard Heloderma suspectum (Gila monster). It mimics the
incretin hormone glucagon-like peptide 1 (GLP1), which stimulates in­
sulin secretion through its G-protein coupled receptor and improves
hyperglycemia in patients with type 2 diabetes [69]. Reports have
shown that in patients with diabetes, GLP1 administration decreases
blood glucose levels; however, owing to its short half-life, this infusion
needs to be administered constantly, a practice not useful for the clinical
treatment of a common condition [69]. The administration of exendin-4
in experimental diabetic models and humans revealed an increase in
insulin secretion, translating into reduced blood glucose and glycosy­
lated hemoglobin levels, thereby improving β-cell sensitivity to glucose.
Therefore, exendin-4 was approved for treating type 2 diabetes in
combination with other drugs, such as metformin and sulfonylureas
[69].
The identification of biologically active animal venom-derived pep­
tides, especially those that impact ion influx, with potential use in
chronic diseases, such as diabetes, is a growing research area. Synthetic
call14.2b (s-call14.2b), a conotoxin in the venom of CaliforniConus cal­
ifornicus, modulates insulin secretion in vitro and in vivo by increasing
CaV1.2/1.3 channel current. This L-type voltage-dependent channel is
involved in β-cell insulin secretion through Ca2+ influx [70]. Similarly,
the neurotoxin Bs-KTx6, found in the venom of B. sindicus, is a selective
inhibitor of the voltage-gated potassium channel KV1.3. Inhibition of
this channel enhances insulin sensitivity caused by an increase in
glucose transporter 4 (GLUT4) on the plasma membrane [71].
Thus, animal venom-derived peptides are promising therapeutic
options for treating diabetes.
5.4. Neurologic and immune regulation
5.4.1. Analgesic, anti-inflammatory, and immune activity regulation
Chronic pain is a common, complex, and distressing problem that has
a profound impact on both individuals and society. It frequently occurs
due to disease or injury. Globally, 30% of the people experience acute or
chronic pain every year, making pain a public health problem. Chronic
pain can have a significant socioeconomic impact owing to the cost of
treatment. Pain can be categorized as nociceptive (from tissue injury),
neuropathic (from nerve injury), or nociplastic (from a sensitized ner­
vous system), all of which affect workup and treatment decisions [72].
Therefore, identifying molecules for pain control (chronic and acute)
with fewer adverse effects and greater effectiveness is imperative. Pep­
tide molecules are more targeted and have fewer side effects than other
small molecules. Therefore, peptides with specific characteristics for
treating pain and inflammation could be a new alternative (Table 2).
Chronic pain causes dysfunction of voltage-gated sodium (NaV)
channels, resulting in complex disorders. Therefore, the identification of
NaV1.7 inhibitors for chronic pain is an area of interest. Spider venom is
a rich source of peptide ion channel modulators with important thera­
peutic potential, and has been pharmacologically characterized. Cd1a
from the venom of Ceratogyrus darlingi [73], phlotoxin 1 (PhlTx1) pep­
tide from Phlogiellus [74]; μ-TRTX-Df1a (Df1a) from D. fasciatus venom
[75]; aranetoxin-Ab1a peptide from the spider Argiope bruennichi [76];
active peptide ω-Avsp1a from Avicularia sp. (“Amazonas Purple,” Peru)
[77]; and v-TRTX-Cc1a (Cc1a), which is 67% identical to the spider
toxin v-TRTX-Hg1a, from the venom of P. muticus [16] are characterized
as modulators of voltage-gated calcium (CaV) channel activity, altering
the activation or inhibiting NaV channels. The Df1a peptide showed
analgesic activity in vivo and reversed spontaneous pain, and the
v-TRTX-Cc1a (Cc1a) peptide preferentially inhibited Ba2+ currents
through L-type CaV channels (CaV1.2 and CaV1.3) heterologously
expressed in Xenopus oocytes [16]. Interestingly, two peptides derived
from the JzTx-V peptide (AM-8145 and AM-0422), obtained from the
venom of the Chinese ground tiger tarantula C. jingzhao, showed
J.L. Díaz-Gómez et al. Biomedicine & Pharmacotherapy 170 (2024) 116015

Fig. 4. Snake venom peptides and their relationship with insulin secretory pathways. (A) Exendin-4 is a peptide in snake venom that mimics GLP-1, a hormone that
activates its receptor (GLP1R: a G-protein coupled receptor) in pancreatic β-cells, promoting cAMP synthesis through the conversion of ATP (obtained from glucose
metabolism, which enters β-cells through GLUT2) by AC. This activates PKA, a protein kinase that phosphorylates the ATP-sensitive potassium channel (KATP),
depolarizing the membrane that opens the CaV1.2/1.3 channel. This increase in intracellular Ca2+ promotes insulin release from β-cells. Synthetic call14.2b (s-
call14.2b), a conotoxin, can stimulate CaV1.2/1.3, promoting insulin secretion. (B) In insulin-sensitive tissues, such as skeletal muscle and adipose tissue, insulin
binding to its putative receptor (INSR) and further activation leads to the phosphorylation of KV1.3. The inhibition of KV1.3 leads to plasma membrane depolar­
ization, which promotes Ca2+ release from cellular repertoires, resulting in the translocation of GLUT4 to the plasma membrane for glucose capture. cAMP: cyclic
adenosine monophosphate; ATP: adenosine triphosphate; ER: endoplasmic reticulum; GLUT2: glucose transporter 2; GLUT4: glucose transporter 4; GL1P: glucagon-
like peptide 1; IG: insulin granule; INSR: insulin receptor; PKA: protein kinase A.

improved NaV selectivity and biological activity in blocking action po­
tential firing in both neurons and C-fibers [78].
In neuropathic pain, P2×3 receptors present changes within lipid
rafts in trigeminal sensory neurons and the dorsal root ganglion, where
they play a key role in sensory transmission, suggesting that sterols have
no direct effect on pore entrance. The peptide PT1, isolated from
A. marikovskyi spider venom, is the first polypeptide compound that
selectively modulated purinergic P2×3 receptors implicated in inflam­
matory pain [72].
PnPP-19 peptide, a molecule with 19-aa residues, shows several
therapeutic characteristics, including pain control. It represents a part of
the primary structure of the toxin δ-CNTX-Pn1c, isolated from the
venom of the spider P. nigriventer. The nociceptive effect induced by
PGE2 was significantly reversed by PnPP-19, and this effect involved the
nitrergic system, which is regulated by KATP activation [79].
Behavioral tests in rats have shown that peripheral and central
antinociception induced by PnPP-19 are due to the activation of
cannabinoid receptors, µ- and δ- opioid receptors [80,81]. PnPP-19
selectively activates µ-opioid receptors, indirectly inducing the inhibi­
tion of calcium channels, thereby impairing calcium influx in dorsal root
ganglion neurons. However, PnPP-19 does not induce β-arrestin
recruitment, highlighting its potential for designing improved opioid
agonizts [81]. Other peripheral antinociceptive molecular mechanisms
for PnPP-19 include reversal of PGE2-induced effects by activating the
NO–cGMP–KATP pathway. These results demonstrate its usefulness in
treating pain and the importance of nNOS and eNOS activation, as well
as endogenous NO release, in inducing peripheral antinociception [79].
Another group of peptides derived from the venom of other species
have shown potential for pain control. For example, the analgesic ac­
tivity of the leptucin peptide derived from the scorpion H. lepturus
venom was tested using both hot plate and tail-flick tests, suggesting
that leptucin acts at supraspinal sites and directly on spinal opioid re­
ceptors [82]. Conotoxin-Ac1, a linear peptide of 15 aa, and its variant
conotoxin-Ac1-O6P, were isolated from the venom duct of Conus acha­
tinus. Electrophysiological results showed that conotoxin-Ac1 inhibited
N-methyl-D-aspartate receptor subunit 2B. Conotoxin-Ab1 and
conotoxin-Ab1-O6P were tested for potential analgesic activity by
interacting selectively with NaV channel subtypes [83,84].
Anti-inflammatory activities of venom-derived peptides have been
studied. For example, the oxidized form of the peptide paulistine, found
in the venom of the wasp P. paulista, inhibits edema and pain caused by
the reduced form of the peptide in vivo. It appears that paulistine exerts

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J.L. Díaz-Gómez et al. Biomedicine & Pharmacotherapy 170 (2024) 116015

Table 2
Bioactivities related to neurologic and immune regulation of animal-derived venom peptides and their mechanisms of action.
Peptide Peptide source Activity Mechanism Reference

Cd1a Ceratogyrus darlingi Analgesic Inhibition of Cav2.2 channel 73

Inhibition of Nav1.1–1.2 and Nav1.7–1.8 channels
PhlTx1 Phlogiellus genus Analgesic 74
Df1a Davus fasciatu Analgesic Modulator of voltage-gated calcium (Cav) and sodium (Nav) 75
channel activity
Aranetoxin-Ab1a Argiope bruennichi Analgesic 76
AM-8145 and AM-0422 Chilobrachys jingzhao Analgesic Modulator of Nav activity 78
PT1 Alopecosa marikovskyi Analgesic Selective modulation of P2×3 receptors 72
PnPP-19 Phoneutria nigriventer Analgesic Regulates the nitrergic system by activation of ATP-sensitive 79, 80, 81
potassium channels (KATP),
activation of cannabinoid receptors, µ- and δ-opioid
receptors
Inhibition of calcium channels
Activation of the NO–cGMP–KATP pathway
Leptucin Hemiscorpius lepturus Analgesic Activates spinal opioid receptors 82
Conotoxin-Ac1 and conotoxin- Conus achatinus Analgesic Inhibits N-methyl-D-aspartate receptor subunit 2B 83, 84
Ac1-O6P Modulator of voltage-gated Nav activity
Paulistine Polybia paulista Analgesic Inhibition of the cyclooxygenase II pathway 85
Anti-Inflammatory
H-TL1 Hydrophis cyanocinctus Anti-Inflammatory Inhibits the interaction between TNF-α and TNF receptor 1 86
Attenuates the cytotoxicity of TNF-α
TnP Thalassophryne nattereri Anti-Inflammatory (multiple Reduced infiltration and activity of macrophages and T cells 88
sclerosis) Promotes emergence of T regulatory cells
Accelerates remyelination
sVmKTx Vaejovis mexicanus smithi Anti-Inflammatory Inhibits Kv1.3 channels of human T cells 87
Reduces the expression of CD40L in human T cells
RegIIA, δ-conotoxins, Conus spp. Motor activity regulation Neuronal nicotinic acetylcholine receptors (nAChRs) 22, 84, 89, 90,
3/5 α-conotoxin, regulation 91, 92
RgIA-5474, Czon1107, CIA,
CIB and hα3β4
Ly6/uPAR protein, SLURP and, Elapidae spp. Myorelaxants and analgesics α-neurotoxin peptides inhibiting nicotinic acetylcholine 93
Lynx1 receptors (nAChRs)
Azemiopsin Azemiops feae Muscle relaxation Selective inhibitor of nAChRs 5, 94
MT9 Dendroaspis angusticeps Arteries myorelaxants Antagonizes muscarinic type 2 receptor and reverses M2R- 96
agonist-induced relaxation
JZTX-V Chilobrachys jingzhao Motor activity regulation Inhibitory effect on NaV1.4 channel 97
ω-Avsp1a Avicularia sp. Analgesic Inhibits T-type CaV3 channel subtypes 77
Motor activity regulation
ω-TRTX-Cc1a Pelinobius muticus Analgesic Based on voltage-gated ion channels 16
Motor activity regulation Effective as an inhibitor of CaV2.3 channels
SVHRSP Buthus martensii Motor activity regulation Regulates inflammatory function of microglial cells 95, 99, 100,104
Karsch Neuroprotection Reduces loss of dopaminergic neurons
Increases viability of BV2 microglial cells
Reduces the expression iNOS, COX-2, Nox2, TNF-α, IL-1β,
and MDA
Regulates autophagy by activating PI3K/AKT/NF-kB
signaling
p-BTX-I Bothrops atrox Antineurodegenerative activity Increases viability, glucose uptake, and differentiation in 101
P12 cells
Induces an increase in the expression of synapsin I, AMPK-α,
β-III-tubulin, and apolipoprotein E
DVPH, VPH, HCTNIF, CTNIF, Daboia russelli russelli Antineurodegenerative activity Protects SH-SY5Y neuroblastoma cells against β-amyloid 102
TNIF and NIF peptides
Disaggregates β-amyloid peptides
Prevents the formation of fully formed β-amyloid fibrils
Octovespin Polybia occidentalis Antineurodegenerative activity Inhibits the aggregation of and degrades β-amyloid plaques 103
in vitro and in vivo
Conantokins Conus spp. Neuroprotection Allosteric antagonists of ion channels of the N-methyl-D- 98
aspartate receptor
Andannulatin Campsomeriella annulata Neuroprotection Increases cell integrity in P12 cells 105
annulata
TPN-RQ Apis mellifera Antidepressant activity Blocks the conductance of ROMK 106

TPN-RQ: tertiapin

its anti-inflammatory activity by inhibiting the cyclooxygenase II
pathway [85]. A study reported the anti-inflammatory activity of a novel
peptide, hydrostatin-TL1 (H-TL1), found in the venom of Hydrophis
cyanocinctus. H-TL1 inhibited the interaction between TNF-α and TNF
receptor 1 and attenuated the cytotoxicity of TNF-α in fibroblast L929
cells [86]. H-TL1 reduced the expression of TNF-α/TNF receptor 1 in
HEK-293 cells. H-TL1 reduced dextran sodium sulfate- and
lipopolysaccharide-induced inflammation in vivo. Transcriptome anal­
ysis of the venom of V. mexicanus smithi led to the identification and
synthesis of the peptide sVmKTx, which exhibited inhibitory activities
against Kv1.3 channels in human T cells and reduced CD40L expression
[87]. Both proteins are important biomarkers and regulators of T-cell
activation through Ca2+ signaling; thus, sVmKTx could be used to
develop drugs to treat autoimmune disorders.
Venom-derived peptides have shown pharmaceutical potential for
treating autoimmune diseases. The TnP peptide, identified in the venom
of T. nattereri, showed anti-inflammatory and immunomodulatory ac­
tivities in an experimental autoimmune encephalomyelitis model in

11
J.L. Díaz-Gómez et al.
mice [88]. This in vivo model was used to simulate multiple sclerosis, an
autoimmune disease characterized by demyelination, neuronal loss, and
progressive neurological disabilities. TnP exerts its anti-inflammatory
activity by decreasing the number of perivascular infiltrates in the spi­
nal cord, decreasing macrophage activity, reducing the infiltration of
IFN-γ-producing Th1 and IL-17A-producing Th17 cells into the central
nervous system, promoting the emergence of regulatory T cells, and
accelerating remyelination in affected tissues [88].
5.4.2. Motor activity regulation
Parkinson’s disease, schizophrenia, and addictive processes of drug
abuse are disorders of the central and peripheral nervous systems. In
these diseases, neuronal nicotinic acetylcholine receptors (nAChRs) play
pivotal roles in regulating transmitter release, cell excitability, neuronal
integration, and motor regulation (Table 2).
The dysfunction of nAChRs has been implicated in various severe
pathologies. Conotoxins, are potent antagonists of various nAChR sub­
types and participate in prey capture through muscle paralysis. Peptides
such as RegIIA [89], CIA and CIB [22], δ-conotoxins [84], 3/5 α-con­
otoxin MilIA [90], RgIA-5474 [91], Czon1107, CIA and CIB [22], and
heterologous hα3β4 [92] have exhibited effective activity. Another
group includes snake venom α-neurotoxin peptides derived from the Ly6
family (Ly6/uPAR protein, SLURP1, and membrane-attached
Ly-6/neurotoxin, Lynx1) that act as myorelaxants and analgesics [93].
Additionally, azemiopsin, a linear peptide from viper venom, is an
effective local muscle relaxant [5,94].
A novel synthetic heat-resistant peptide derived from scorpion
venom (SVHRSP) has been reported to exert protective effects against
attenuated dopaminergic neurodegeneration and motor dysfunction
[95]. MT9, a natural peptide derived from mamba venom, antagonizes
the muscarinic type 2 receptor and reverses M2R-agonist-induced
relaxation in human arteries [96].
Mechanisms of action other than nAChRs involve voltage-gated ion
channels, which are critical for controlling the function of excitable
cells. Human genetic studies have shown that the aberrant function of
these channels causes channelopathies, including epilepsy, arrhythmia,
paralytic myotonia, and pain [97]. The effects of peptide toxins have
shed light on the structure–function relationships of these channels. For
example, increased T-type calcium currents are found in various path­
ological conditions owing to the upregulation of specific CaV3 subtypes.
Tarantula venom ω-Avsp1a inhibited specific T-type CaV channel sub­
types [77].
Similarly, conanokines function as allosteric antagonists of N-
methyl-D-aspartate receptor ion channels. These receptors have
considerable functional plasticity depending on their subunit combina­
tion, which are regionally and developmentally controlled in the brain
[98]. In the search for subtype-selective blockers of CaV channels, the
peptide ω-TRTX-Cc1a from tarantula venom was effective as an inhibitor
of CaV2.3 channels [16].
Functional NaV channels are involved in regulating microglial
function and inflammation associated with the pathology of Parkinson’s
disease. Here, SVHRSP inhibited neuroinflammation and protected
dopaminergic neurons by downregulating microglial cells [99,100].
5.4.3. Protection against dementia-related neurodegeneration
Venom-derived peptides show neuroprotective activity in AD-
mediated damage mechanisms. Cell-protection activities have been re­
ported in PC12 cells treated with a synthetic peptide (p-BTX-I) found in
B. atrox (a venomous pit viper) venom and exposed to acrolein, a
chemical that causes neural damage similar to that observed in AD
[101]. Treated PC12 cells had higher viability and differentiation
(developing neurites) and showed an increase in glucose uptake
compared with untreated cells. p-BTX-I induced an increase in the
expression of proteins related to metabolism, communication, cell
structure, and removal of amyloid aggregates, such as synapsin I,
AMPK-α, β-III-tubulin, and apolipoprotein E. A study analyzed six
12
Biomedicine & Pharmacotherapy 170 (2024) 116015
synthetic peptides derived from Russell’s viper venom factor V activator,
an proteolytic enzyme in the venom of Daboia russelli russelli. Russell’s
viper venom factor V activator was subjected to enzymatic hydrolysis
and fractionation, and the ability of several resulting fractions to
disaggregate β-amyloid peptides was evaluated. A highly active fraction
was identified, and its peptide sequence, determined in silico, was used
to design six peptides. These peptides were synthesized to have sequence
homology with the hydrophobic region (QKLVFFA) of β-amyloid pep­
tides, and their ability to disaggregate them in vitro was evaluated. The
results showed that the synthetic peptides protected SH-SY5Y neuro­
blastoma cells against the cytotoxicity of β-amyloid peptides. The
venom-derived peptides disaggregated β-amyloid peptides in a
dose-dependent manner. Incubation of SH-SY5Y cells with synthetic
peptides and β-amyloid peptides prevented the formation of fully
formed β-amyloid fibrils and their internalization into the cells,
compared with the negative controls [102].
Octovespin, a peptide derived from wasp venom (Polybia occidenta­
lis) could inhibit the aggregation and the activity to degrade β-amyloid
plaques in vitro and in vivo. Octovespin decreased the aggregation of
β-amyloid peptides, but was unable to disaggregate them during in vitro
kinetic assays. Mice treated with octovespin and exposed to β-amyloid
peptides retained memory functions similar to those of healthy mice
compared with the untreated group. However, in vivo experiments
showed a statistically significant improvement over disease control in
two of the four behavioral experiments, and histological analysis of the
hippocampus showed no statistical difference in neurotoxicity and
β-amyloid peptide formation between the control and treatment groups
[103].
These studies indicate the potential of venom-derived peptides in
preventing β-amyloid plaque formation and as neuroprotective agents in
AD. However, the mechanisms involved should be investigated, and
their bioactivities must be evaluated during in vivo experiments to
validate their pharmacokinetics and pharmacodynamics.
5.4.4. Antineurotoxic
Venom-derived peptides have shown protective activities against
neurotoxic agents such as PM2.5 (a neurodegenerative air pollutant). In
an in vitro study using BV2 microglial cells, SVHRSP increased cell
viability after PM2.5 exposure [104]. After pollutant exposure, the
peptide induced M2 activation of microglial cells, as it reduced the
expression of cytotoxic factors, such as iNOS, COX-2, Nox2, TNF-α,
IL-1β, and malondialdehyde. Furthermore, SVHRSP regulated auto­
phagy in BV2 cells, due to the management of TLR-4 by activating the
PI3K/AKT/NF-kB signaling pathway.
Three bioactive peptides were found in the venom of the solitary
scoliid wasp Campsomeriella annulata annulata. These peptides were:
α-campsomerin, β-campsomerin, and annulatin, with annulatin being
the only ɑ-helical peptide. Only α-campsomerin increased the integrity
of P12 cells after 24 and 48 h of exposure; however, none of the tested
peptides protected neuronal cells against oxidative stress produced by
H2O2 [105].
Thus, venom-derived peptides have neuroprotective properties.
Further studies must evaluate the mechanisms by which they exert their
effects and their application against several neurotoxic factors.
5.4.5. Antidepressive
The possible applications of venom-derived peptides are not limited
to dementia and motor disorders, pain reduction, or neuroprotection,
but also in reducing the symptoms of depression in vivo.
Honeybee venom peptides synthesized using a cellulose membrane-
based spot-synthesis method exhibited several antidepressant activities.
This peptide blocked the conductance of ROMK, a K+ rectifier channel,
using tertiapin and its derivative peptides in vitro. In vivo experiments
using mice showed that intracerebroventricular administration of this
peptide reduced the level of depressive behaviors, but increased some
anxiety-like symptoms [106]. Further studies are required to explore the
J.L. Díaz-Gómez et al. Biomedicine & Pharmacotherapy 170 (2024) 116015

potential of venom-derived peptides to develop antidepressants. Table 3

Antimicrobial activities of animal venom-derived peptides.
5.5. Activities against pathogenic microorganisms Peptide Peptide source Antimicrobial Specific Reference
activity microorganism
5.5.1. Antibacterial Anoplin Anoplius Antibacterial Pseudomonas 17
Antimicrobial resistance is a global concern. AMPs are alternatives analogs samariensis aeruginosa,
for treating antimicrobial-resistant infections. Therefore, animal venom- Escherichia coli,
and Zymomonas
derived peptides have received significant attention as potential candi­
mobilis
dates for developing synthetic peptides or analogs as new antimicrobial PV and Bothrops asper Antibacterial P. aeruginosa, 107
agents (Table 3). PV3 Acinetobacter
Anoplin is a potent, short, natural, cationic AMP isolated from the baumanii,
venom of the solitary wasp A. samariensis. The antimicrobial activities of Staphylococcus
aureus, and
various lipophilic analogs of anoplin have been evaluated against gram-
Enterococcus
negative and gram-positive bacteria. These analogs exhibited significant faecalis
activity against Pseudomonas aeruginosa, E. coli, and Zymomonas mobilis, MP-V1 Vespula Antibacterial Streptococcus 108
owing to the increased amphipathic character of the peptide. All the vulgaris mutans and
Salmonella
synthetic peptides showed low hemolytic activity and were stable in
enterica
proteolysis tests, suggesting that lipophilic groups play a key role in the GI24 PMAP-36 Antibacterial E. coli 109
proteolytic resistance of peptides [17]. (porcine
Short hybrid peptides derived from pEM-2, mastoparan-VT1, and cathelicidins)
mastoparan-B (previously reported synthetic peptides), were designed StigA6 Tityus Antibacterial E. coli, 110
and stigmurus Enterobacter
to characterized their antimicrobial activity. All the peptides showed
StigA16 cloacae,
good antimicrobial activity against the gram-negative bacteria P. aeruginosa,
P. aeruginosa, Acinetobacter baumanii, S. aureus, and Enterococcus faecalis. S. aureus,
Hybrid peptides, designed for greater amphipathicity, could be used to Staphylococcus
epidermis, and
develop novel antimicrobial agents with improved activity and selec­
E. faecalis
tivity, mainly PV and PV3, derived from pEM-2, which is sourced from Css54 Centruroides Antibacterial Listeria 111
Bothrops asper [107]. suffusus monocytogenes,
MP-V1 is a de novo type of mastoparan peptide derived from the Streptococcus suis,
venom of the social wasp Vespula vulgaris. MP-V1 showed strong anti­ Campylobacter
jejuni and
microbial activity against Streptococcus mutans and Salmonella enterica
Salmonella
and antifungal activity against C. albicans. However, minimal cytotox­ typhimurium
icity was observed in human erythrocytes. This suggests that MP-V1 is a Peptide- Vespa orientalis Antibacterial E. coli, 112
promising candidate for developing new antimicrobial agents, attrib­ AuNPs S. typhimurium
utable to the amphipathic characteristics of the peptide [108]. and K. pneumonia
Uy243, Urodacus Antibacterial E. coli, S. aureus, 113
Derived from the AMP PMAP-36, the 24-residue truncated peptide Uy17, yaschenkoi Burkholderia
GI24 showed high antimicrobial activity and low hemolytic activity, Uy192 silvatlantica and
suggesting that it has optimal cell selectivity. The antimicrobial mech­ and Streptococcus spp.
anism occurred by damaging cell membrane integrity through perme­ QnCs-
BUAP
ability (tested in E. coli); increasing the hydrophobicity of this peptide
Ocellatin- Ceratogyrus Antiviral Rabies virus 116
did not increase antimicrobial activity [109]. P1 darlingi
Analogs of stigmurin, extracted from T. stigmurus, had higher anti­ ZY13 Bungarus Antiviral Zika virus, 117
bacterial activity than the naive molecule. StigA6 and StigA16 peptides fasciatus Influenza virus
had lower minimum inhibitory concentration against E. coli, Entero­ Polybia- Polybia paulista Antifungal, Candida spp., 31, 119
CP Antiprotozoal Plasmodium
bacter cloacae, P. aeruginosa, S. aureus, Staphylococcus epidermis, and gallinaceum
E. faecalis. Rational design was based on an increase in net charge and Kn2-7 Mesobuthus Antifungal Candida albicans 120
hydrophobic moment [110]. martensii
The Css54 peptide, extracted from the venom of Centruroides suffusus, Lycosin-II Lycosa Antifungal Candida spp. 118
singoriensis
showed antibacterial activity against Listeria monocytogenes, Strepto­
ToAP2 Tityus obscurus Antifungal Candida spp., 121
coccus suis, Campylobacter jejuni, and Salmonella typhimurium. A notable Cryptococcus
advantage of this peptide is its low cytotoxic effect on mammalian cells neoformans
compared with that of melittin, which was used as the control. Inter­ GK-19 Androctonus Antifungal C. albicans 122
estingly, the Css54 peptide functioned as an antibiofilm agent against amoeruxi
MP-VT1 Vespa tropica Antifungal C. albicans 123
L. monocytogenes. These data support the use of Css54 as an alternative XYP1 L. coelestis Antiprotozoal Toxoplasma gondii 124
antibacterial agent [111]. Pep1, Tityus Antiprotozoal T. gondii 125
Other strategies suggest the synergistic effects of various molecules, Pep2a, serrulatus
compromising the extracted peptide. Gold nanoparticles functionalized and
Pep2b
with a peptide extracted from Vespa orientalis wasp venom demonstrated
M- Dinoponera Antiprotozoal Trypanosoma 115
antimicrobial activity; however, their use with other antimicrobial PONTX- quadriceps cruzi
compounds enhanced their antimicrobial effects. The new conjugate Dq3a
(peptide and gold nanoparticles) demonstrated high antibacterial ac­ CM11 Hyalophora Antiprotozoal Entamoeba 28, 126,
tivity against E. coli, S. typhimurium, and Klebsiella pneumonia [112]. cecropia and histolytica, 127, 128
Apis mellifera Blastocystis,
Three AMP’s derived from U. yaschenkoi: Uy243, Uy17, and Uy192, Leishmania major
and a peptide designed from an AMP (QnCs-BUAP) showed high anti­
(continued on next page)
bacterial activity in a stand-alone experiment. However, a synergistic
effect was observed when both were combined. Combinations of the

13
J.L. Díaz-Gómez et al.
Table 3 (continued )
Peptide Peptide source Antimicrobial Specific Reference
activity microorganism
pCergo, Cerrophidion Antiprotozoal L. major 48
pBmTxJ godmani,
and Bothrops
pBmje moojeni,
Bothrops
marajoensis
peptides were tested against E. coli, S. aureus, Burkholderia silvatlantica,
and Streptococcus spp. isolated from clinical multidrug-resistant strains
[113].
However, studies have shown that not all natural peptide analogs
have positive effects as AMPs. Synthetic analogs of eumenine masto­
paran peptides were tested for antimicrobial activity. In this study, wasp
venom-derived peptides exhibited antimicrobial activity; however,
compared with their analogs, only the original peptide had antimicro­
bial activity. An unexpected result was that the analogs were synthe­
sized to avoid affecting the basic structural requirements of AMPs,
resulting from a rational design approach [114].
The trypanocidal activity of peptides derived from Dinoponera
quadriceps venom was evaluated. Two fragments derived from the AMP,
M-PONTX-Dq3a, were identified as potent trypanocidal agents against
Trypanosoma cruzi, the causative agent of Chagas disease. The peptides
were a better option than the standard-of-care drug benznidazole for
treating benznidazole-resistant strains [115].
5.5.2. Antiviral
Animal venoms and secretions have long been studied as new
bioactive molecular sources, presenting a wide spectrum of biological
effects, including antiviral activity, and are important resources for
developing new drugs [116,117]. Natural animal host defense peptides,
which have evolved to protect hosts, possess antiviral properties [117].
Amphibian skin secretions are a rich source of bioactive molecules,
including those with antiviral activities. Ocellatin-P1, a peptide isolated
from Leptodactylus labyrinthicus venom, inhibits rabies infection in BHK-
21 cells. This virus has a single, non-segmented, negative-strand in its
RNA genome, which encodes five proteins: nucleoprotein, RNA-
dependent RNA polymerase, phosphoprotein, matrix protein, and
glycoprotein. Glycoprotein is a membrane protein that forms trimers on
the viral surface and the major antigen responsible for inducing the
production of virus-neutralizing and protective antibodies located in the
C-terminal region of the peptide. A fraction of the pure synthetic peptide
was de novo sequenced and identified as ocellatin-P1 (GVVDILK­
GAAKDIAGHLASKVMNK) and aligned with NSRG (G region) of the
RABV glycoprotein, which is associated with cell penetration and
maintains the synergistic antiviral activity displayed by the full peptide
and the alkaloid bufotenine, isolated from Anadenanthera colubrina seeds
[116].
Cathelicidin-BF (BF-30) is a defensive peptide identified from
B. fasciatus snake venom. ZY13, a peptide analog of cathelicidin-BF,
inhibited ZIKV infection in vitro in U251 and Vero cells and in vivo in
1-d-old Balb/c mouse pups by reducing infectious virions and
strengthening host antiviral immunity through suppression of the
cytokine signaling protein (AXL-SOCS) pathway. In addition, it has
strong activity against Propionibacterium acnes and influenza A virus
[117].
5.5.3. Antifungal
Antimicrobial resistance poses a severe threat to public health and
necessitates developing effective drugs to combat infection. Fungal in­
fections, such as candidiasis, are becoming increasingly problematic.
Three classes of antifungal agents: azoles, polyenes, and echinocandins,
are used in clinical settings [118]. Candida infections have the highest
incidence of all invasive fungal infections. Candidiasis involves
14
Biomedicine & Pharmacotherapy 170 (2024) 116015
infections ranging from superficial, such as oral thrush and vaginitis, to
systemic, and potentially life-threatening diseases [119].
Candidemia is the fourth most common nosocomial bloodstream
infection. Recent surgery and long-term catheterization are common
risk factors for developing systemic candidiasis [120].
C. albicans is an opportunistic fungal pathogen that causes nosoco­
mial bloodstream infections, with a mortality rate of 40%, despite the
use of antifungal agents. C. albicans can cause superficial infections in
patients who are immunocompromised and are undergoing organ
transplantation and chemotherapy [118].
The AMP polybia-CP (ILGTILGLLKSL-NH2) was isolated from the
venom of the social wasp P. paulista. Polybia-CP exhibits antifungal
activity through a multiaction mechanism that disturbs membrane
integrity and interferes with mitochondrial function [119]. Polybia-CP
can bind fungal cell wall polysaccharides, because preincubation with
peptides and polysaccharides significantly decreased the antifungal ef­
fects of this peptide. In addition, it induces an increase in cellular ROS
production, which may contribute to its antifungal activity [119].
The AMP BmKn2 is a peptide isolated from M. martensii scorpion
venom, and three uncharged amino acid residues in BmKn2 were
substituted with positively charged residues to create Kn2–7. The
binding of Kn2–7 to bacterial surface molecules leads to rapid (<2 min)
cell wall and membrane disruption, providing a distinct advantage over
triazoles and echinocandins, which may take a day or longer to induce
significant killing, because their targets are directed at metabolic pro­
cesses [120].
Lycosin-II, a 21-aa peptide isolated from the venom of the spider
L. singoriensis, inhibits biofilm formation by C. albicans and multispecies
biofilms. Lycosin-II has antifungal activity, and its mechanism of action
includes depolarization of the cytoplasmic membrane, which induces
membrane permeation. Excessive production of ROS induced by anti­
fungal agents affects lipid retention and induces membrane permeability
[118].
The peptides ToAP2, ToAP2S1, ToAP1, ToAP3, and ToAP4 from the
venom of the scorpion Tityus obscurus, were the first AMPs characterized
in this species. They adopt a helical conformation, with distinct hydro­
phobic and hydrophilic faces. All the peptides tested reduced biofilm
formation in both the initial cell adherence and mature phases. ToAP2
was the most active peptide at two different stages of biofilm formation,
presenting a lower effective concentration than other peptides. These
peptides showed antifungal effects in different phases of biofilm for­
mation at lower concentrations than expected for prospective antifun­
gals (100–1000 times higher than the concentrations used against
planktonic cells) [121].
Androctonus amoreuxi AMP1 (AamAP1), identified from the venom-
derived cDNA library of the North African scorpion A. amoreuxi, is a
new type of host defense peptide. GK-19, a new scorpion venom AMP,
derived from AamAP1, disrupts the fungal membrane and cell wall
structure and exhibits potent and rapid antibacterial and antifungal
activities by permeabilizing microbial membranes. GK-19 can induce
pore formation through its interaction with the cellular membranes of
both bacteria and fungi, suggesting that it may not induce drug resis­
tance [122].
Astoparan VT-1 (MP-VT1), a tetradecapeptide isolated from the
venom of the social wasp Vespa tropica, has several antifungal effects.
MP-VT1 penetrated well inside the biofilm, where it exerted candida­
cidal activity and obliterated the planktonic cells of C. albicans; how­
ever, it profoundly reduced the viability of biofilm-enclosed cells.
Notably, MP-VT1 showed faster candidate acidity than fluconazole. The
disruption of cell membrane integrity is the principal antifungal mech­
anism of MP-VT-1, culminating in the death of C. albicans, mainly by
necrosis [123].
5.5.4. Antiprotozoal
Different parasitic infections affect humans and are associated with
public health problems. Consequently, venom-derived peptides have
J.L. Díaz-Gómez et al.
been studied for their potential to destroy different life stages of para­
sites that cause diseases in humans. The need to develop new therapies
with fewer adverse effects has led to the study of new molecules with
potential antiparasitic effects. The main venom-derived peptides with
antiparasitic activities and their mechanisms of action are discussed in
this section (Table 3).
Toxoplasma gondii is an obligate intracellular parasite that causes
toxoplasmosis in humans. As with other antiparasitic drugs, toxoplas­
mosis treatments are significantly toxic, and no vaccine is available
[124]. XYP1, a synthetic peptide identified in the venom glands of the
spider Lycosa coelestis, was tested in vitro using T. gondii-infected human
foreskin fibroblasts and in vivo using an infected BALB/c mouse model
[124]. In vitro studies showed that XYP1 inhibited the viability, inva­
sion, and proliferation of T. gondii tachyzoites and presented low toxicity
toward human host cells. In vivo studies showed that XYP1 increases the
survival rate of infected mice. Possible mechanisms of action that
explain the antiparasitic activity of XYP1 include membrane perfora­
tion, swelling, and tachyzoite disruption. Finally, the possible mecha­
nism of action of this peptide includes a reduction in the expression of
proinflammatory biomarkers IL-6 and IL-8 in human foreskin fibroblasts
and reduction in mRNA expression of T. gondii HSP29, which is an
important cell membrane protein. The bioactivity of Pep1, Pep2a, and
Pep2b, derived from an isolated fraction of the toxin Ts2 from the
scorpion T. serrulatus venom, against toxoplasmosis was evaluated
[125]. These peptides have been studied in vitro and in vivo. Pep1 and
Pep2a reduced tachyzoite replication in macrophages in vitro, whereas
Pep2 increased parasite replication. However, all three peptides
decreased the number of cerebral cysts and did not induce toxicity in
BALB/c mice. Although cytokines involved in innate immunity, such as
IFN-γ and IL-12, were not highly produced in the sera of peptide-treated
mice, it is possible that in specific tissues these peptides induced an
increase in proimmune cytokines production.
T. cruzi, which causes Chagas disease, has two clinical phases. The
chronic phase does not have an effective treatment and causes serious
cardiopathies, thus providing an opportunity to develop new treatments
[115]. Peptide fragments and analogs of M-PONTX-Dq3a (identified
from D. quadriceps ant venom) were synthesized and tested against
T. cruzi strains [115]. M-PONTX-Dq3a [1–15] and [Lys]
3-M-PONTX-Dq3a [3–15] variants showed comparable trypanocidal
activity to the parent peptide. Both peptides were stable in human
serum, permeated LLC-MK2 kidney cells, and exhibited low toxicity in
mammalian cells. Both peptides appear to induce cell death by necrosis,
observed as a loss of cell membrane integrity in T. cruzi epimastigotes.
Amebiasis is an important enteric parasitic infection and one of the
main causes of parasite-related deaths. Amebiasis is caused mainly by
Entamoeba histolytica, and one of the problems with treating this parasite
is its contraindications and adverse effects. Therefore, new bioactive
molecules, including peptides, have been developed. CM11, a cecro­
pin–melittin hybrid peptide, is cytotoxic to E. histolytica cells in a dose-
dependent manner, showing high toxicity at high doses, compared with
metronidazole, and inducing late-phase apoptosis in Caco2 cells [28].
These cell membrane-disruptive effects were less evident in human
Caco2 cells, indicating a specific toxic effect on parasitic cells. These
toxic effects on the cell membranes of the amoeba may be attributed to
their cationic and amphipathic properties. CM11 has not only been
tested for its activity against E. histolytica, but also against other pro­
tozoans. CM11 exhibited cytotoxicity against Blastocystis, a parasite that
causes gastrointestinal disorders. Similar to metronidazole, this effect
was exerted in a dose-dependent manner in vitro with and without
Caco2 cell coculture [126]. In Blastocystis, CM11 seems to induce cell
membrane disruption. CM11 showed cytotoxicity against promastigotes
and amastigotes of Leishmania major [127,128]. CM11 showed a
dose-dependent antileishmanial effect, which was sustained after 48 and
72 h, and a synergistic effect with curcumin [128]. The peptide acted
through a "carpet-like" mechanism by thinning and disrupting the cell
membrane. Other synthetic peptides: pCergo, pBmTxJ, and pBmje,
15
Biomedicine & Pharmacotherapy 170 (2024) 116015
derived from three amino acid sequences of Asp49 PLA2s from snake
venom, were studied for their antileishmanial effects [48]. pCergo
exerted cytotoxicity against the promastigotes of Leishmania braziliensis
and Leishmania amazonensis. Similar to many other AMPs, cell mem­
brane disruption seems to be the main mechanism of their antiparasitic
activity.
The antimalarial activity of venom-derived peptides has been eval­
uated. Polybia-CP, a wasp venom peptide, was used to design less toxic
peptide analogs with increased antimicrobial properties, based on
physicochemical characteristics [31]. These peptides showed cytotox­
icity against Plasmodium gallinaceum sporozoites and are used as thera­
peutic agents in malaria treatment. Although their mechanism of action
has not been elucidated, net positive charge, presence of ɑ-helix struc­
tures, and reduction of hydrophobic residues within the peptide struc­
ture are important characteristics for increasing their antimalarial
activity.
Although some venom-derived peptide characteristics and cell
membrane interactions have been demonstrated to be important for
venom-derived peptides, more studies are needed to understand their
mechanisms of action against parasites. Finally, in vivo studies are
required to assess their antiparasitic activities, side effects, and
pharmacokinetics.
5.6. Other relevant bioactivities
5.6.1. Antivenom activity
Antivenom treatment is crucial for managing envenomation. Animal
venoms exert various effects [13,129–131], and treatments and thera­
pies are adapted based on the venom.
Metalloproteinases, one of the primary components of the Russell’s
viper venom, causes tissue damage and can be targeted by antivenoms.
Newly discovered metalloproteinase inhibitors are effective in blocking
the toxic effects of venom, suggesting their potential use in developing
antivenom therapies [129].
The use of synthetic peptides in antivenom therapy is another
approach. A study in mice showed that use of synthetic epitopes to elicit
an immune response protected against lethal doses of Crotalus durissus
snake venom. Liposomes are used to deliver synthetic epitopes, which
improves their efficacy as immunogens [131].
Several studies have focused on identifying B-cell epitopes in animal
venom-derived proteins. For example, a study identified B-cell epitopes
of a metalloproteinase found in B. atrox snake venom that could be used
to produce venom-neutralizing antibodies [13]. Another study identi­
fied linear B-cell epitopes in three phospholipase A₂ molecules found in
the venom of the snake Bothrops jararacussu. These epitopes were
recognized by a commercial horse antivenom, indicating their potential
use in developing effective antivenom therapies [130].
Overall, the use of various approaches to develop effective anti­
venom treatments depends on venom source and mechanism of action.
The discovery of inhibitors and epitopes, as well as the use of synthetic
epitopes and targeted immunotherapy, can help improve the effective­
ness and availability of antivenom treatments.
5.6.2. Regulation of human reproductive physiology
In terms of human reproduction, venom peptides are involved in
sperm motility and male erectile function. In the first case, a study on
spermaurin, an La1-like peptide from the venom of the scorpion
S. maurus palmatus, identified a potent disulfide-rich 73-aa peptide that
significantly improved the motility of fresh and freeze-thawed sperm in
different mammalian species, including humans, and improved fertil­
ization outcomes in mouse in vitro [132]. The second reported case
involved a peptide derived from the venom of the Egyptian black snake
W. aegyptia. This peptide could activate sperm motility in vitro in male
mice. The peptide is 57-aa long and contains three disulfide bridges
identical to the sequence of Wa Kunitz-type protease inhibitor II. This
peptide belongs to a family of compounds that regulates and controls
J.L. Díaz-Gómez et al.
sperm motility [15].
For erectile function, a newly designed peptide was generated based
on the neurotoxin δ-CNTX-Pn1c from the venom of the “armed” spider
P. nigriventer. The synthesized peptide PnPP-19 potentiated erectile
function not only after subcutaneous or intravenous administration, but
also after topical application. PnPP19 potentiates erectile function
through nitric oxide activation, indicating that PnPP-19 activates the
NO/cGMP pathway by activating nNOS and iNOS [133–135].
5.6.3. Eye function regulation
Venom-derived peptides have been studied to develop treatments for
ophthalmological diseases, usually pathologies that affect the flow of
corneal and aqueous humor. For example, the protective effects of
Pnpa11 and PnPa13 (derived from P. nigriventer spider venom) against
blue light exposure in the retina were evaluated in in vitro and in vivo
models [136]. Neither peptide showed cytotoxic effects on the retinal
cell line ARPE-19. In a degeneration assay, Pnpa11 and PnPa13 reduced
angiogenesis in the retina of rats exposed to blue light. Angiogenesis has
been reported to increase in several retinal diseases, such as diabetic
retinopathy [136]. In the same study, intravitreal injection of both
peptides in a rat model prevented retinal degeneration by inhibiting
retinal damage and apoptosis and reducing the loss of light receptor
cells. PnPa11-treated retinas showed increased Erk1/2 phosphorylation,
inducing NR2A retinal expression, and inhibited Akt dephosphorylation,
whereas PnPa13 prevented Erk1/2 and Akt1 dephosphorylation and
inhibited N-methyl-D-aspartate receptor subunit 2B expression. NR2A
stimulates cell survival and the activation of N-methyl-D-aspartate re­
ceptor subunit 2B induces cell apoptosis. These results suggest that
PnPa11 and PnPa13 stimulate cell survival and reduce programmed cell
death in retinal cells through Akt activation, which suppresses cell
apoptosis.
PnPP-19, a peptide isolated from P. nigriventer venom (see Section
6.6.2), was developed as treatment for glaucoma—a neuropathology
characterized by an increase in intraocular pressure that damages the
optic nerve and can cause blindness [135,137]. PnPP-19 was tested in
hypertensive and nonhypertensive eyes in a rat model [138]. PnPP-19
did not show any toxicity in vitro or in rat’s 0 retinas and corneas
with or without intraocular hypertension. Additionally, PnPP-19
reduced intraocular pressure (approximately 20% for 24 h) in normo­
tensive and ocular hypertensive rats and prevented optic nerve and
retinal damage in hypertensive rats. PnPP-19 increased NO production
in ocular tissue. NO is a potent vasodilator that can reduce intraocular
pressure, because it relaxes the trabecular meshwork and Schlemm’s
canal cells, thus increasing aqueous humor outflow [138].
LyeTxI-b, derived from the toxin LyeTxI found in the venom of the
spider Lycosa eritrognatha, has been synthesized and studied for
ophthalmological applications [139,140]. The peptide did not affect
ARPE-19 cell viability. Intravitreal injection of LyeTxI-b did not cause
retinal damage, although it penetrated the tissue. In addition, LyeTxI-b
did not cause changes in intraocular pressure. LyeTxI-b was tested using
the chorioallantoic membrane method, demonstrating its potential to
prevent neovascularization—examination of rabbit retinas revealed no
change in vascularization. However, the mechanism responsible for the
bioactivity of LyeTxI-b was not reported [140].
The potential uses of toxin-derived synthetic peptides are not well
understood. Important bioactivities in ocular tissues in vivo have been
demonstrated; however, further studies are necessary. Additionally,
preclinical and clinical analyses must elucidate and assess the pharma­
cological efficacy, mechanism of action, and long-term safety of venom-
derived peptides.
5.6.4. Regulation of coagulation and platelet aggregation
Anticoagulant, fibrinolytic, and antithrombotic effects are important
pharmacological uses of venom-derived peptides. One example is the
anticoagulant activity of a peptide (with sequence TNGYT) derived from
the venom of Scolopendra subspinipes mutilans, a type of centipede [141].
16
Biomedicine & Pharmacotherapy 170 (2024) 116015
Peptide fractions were isolated from this venom, and a highly bioactive
peptide sequence was identified. The peptide fractions and pure peptide
increased partial thromboplastin time (aPTT) and prothrombin time in
vitro. The peptide prolonged aPTT ex vivo in a rat model, increased
bleeding and clotting times in vivo, and inhibited coagulation factor Xa.
Blood coagulation factor Xa is a key enzyme in the coagulation cascade,
both in the extrinsic and intrinsic pathways, and converts prothrombin
to thrombin with the assistance of cofactor Va. This inhibition appears to
be the main mechanism of action of the centipede venom peptide
TNGYT [141].
Other venoms that act as anticoagulants include those found in
snakes. For example, the peptide SP-14, identified from the hydrolysate
of Agkistrodon acutus venom after enzyme hydrolysis, exhibited antith­
rombotic activity in a dose-dependent manner. An in vitro study re­
ported that venom hydrolysates generated by pepsin treatment, its
subsequent isolated fractions and SP-14, presented platelet anti­
aggregation activities. SP-14 exerted 80% protection in an ADP-induced
acute pulmonary thrombosis model in vivo. SP-14 increased bleeding
time in vivo, but to a lesser extent than the positive control, and reduced
thrombus weight in an arteriovenous shunt thrombosis model. Because
SP-14 only inhibited U46619-induced platelet aggregation, SP-14 could
block the binding of thromboxane A2 to the TP receptor [142].
Lebetins, derived from the venom of V. lebetina, exhibit platelet
antiaggregation activities. Synthesized lebetins sL2α and sL2β inhibited
ADP-induced platelet aggregation in vitro [20]. Their activities can be
explained by the presence of two arginine–glycin–aspartic acid-like
motifs, essential for platelet surface interactions with extracellular li­
gands to initiate coagulation. Both peptides showed sequence similarity
to NPs, indicating another possible mechanism of cardiovascular regu­
lation. The importance of natriuretic-like peptides and their activities
are detailed in Section 5.2.1. Further studies are required to understand
the interactions between venom-derived peptides and blood coagulation
regulators. Nevertheless, owing to the known effects of the venoms used
to obtain these peptides and the peptides themselves, they are important
candidates for developing anticoagulants.
5.6.5. Renal function regulation
Polycystic kidney disease (PKD) is a genetic disorder in which mul­
tiple cysts grow in the kidneys, leading to end-stage renal failure.
Elevated expression of type-2 vasopressin receptor has been observed in
human ADPKD and animal models. Mambaquaretin-1 is a peptide
derived for green mamba venom. It strongly antagonizes type-2 vaso­
pressin receptor and has therapeutic potential in PKD. Venom compo­
nents principally target enzymes and ion channels involved in the
control of hemostatic, nervous, and cardiovascular systems [143].
5.6.6. Drug delivery
CPPs can cross the cell membrane. This unique feature can be used to
deliver compounds, such as proteins, peptides, oligonucleotides, quan­
tum dots, polysaccharides, chemotherapeutic drugs, polymers, or mol­
ecules, to intracellular compartments. One potential therapeutic option
is developing CPPs for drug delivery. The MCa peptide displayed in vitro
and in vivo stability following intravenous injection into mice, indi­
cating its potential use as a CPP [144].
6. Limitations
This study focused on the potential biomedical applications of
venom-derived synthetic peptides based on the literature reported in the
last decade. However, specific areas of study were not fully covered in
this manuscript and should be addressed in future reviews. Regarding
the separation, isolation, identification, and synthesis of venom-derived
peptides, only the main techniques used to identify and synthesize
peptides are summarized. An in-depth summary and analysis would be
necessary to understand the methodologies, their advantages and areas
of improvement for bioactive peptide research, which was not the
J.L. Díaz-Gómez et al.
objective of this review. Regarding antimicrobial activities, this review
focused on some clear examples of antifungal, antiviral, and anti­
protozoal activities; however, it did not cover all reported antimicrobial
activities of venom-derived peptides, because one of the aims of this
review was to address the bioactivity and potential biomedical appli­
cations of synthesized animal venom-derived peptides. Finally, this re­
view did not describe clinical study reports that evaluate the
bioactivities and biomedical properties of venom-derived peptides,
because it focused only on in vitro and in vivo studies.
The public perception of the use of venom therapy is a problem. This
means that therapeutic treatments with most nonpure venom molecules
could be considered irrational and esoteric by most educated people
[145]. Therapy with poisons of nonpure molecules cannot be considered
a viable treatment option because the acceptance of these products for
medicinal purposes is very low. Therefore, it is imperative to purify and
obtain pure molecules, as is the case of peptides. Given that there are
limited, reasonable, evidence-based medicinal uses of poison products,
it seems important to educate patients and physicians about their limi­
tation of use. Additionally, the manufacturers must use animals hu­
manely and ethically. Testing and production must be maintained and
performed in accordance with nationally and internationally accepted
ethical standards and permissions obtained from local committees
(private or public) in accordance with ethical approvals obtained from
responsible authorities in the jurisdiction [146].
7. Conclusions
Noncommunicable diseases constitute a heterogeneous group that
includes important causes of mortality, such as ischemic heart disease,
diabetes, cancer, and disabilities, such as mental disorders. They require
the search for effective, safe, and cost-effective treatments. Peptides of
animal origin promise to be an important source of molecules with
therapeutic potential. The various bioactive and therapeutic properties
of venom-derived peptides have been studied in a wide range of disease
models, both in vitro and in vivo. These have numerous advantages over
antibodies owing to their smaller size, easier synthesis, and ability to
penetrate the cell membrane. Their roles in cancer include the transport
of radionuclides, cytotoxic drugs, hormones, and vaccines. Biologically
active CPPs constitute an emerging class of therapeutic agents found in
wasp venom. Mastoparan is an established CPP that modulates mito­
chondrial activity and triggers caspase-dependent apoptosis in cancer
cells.
Candidates for developing antihypertensive and cardiovascular
modulators and therapeutics have been reported for venom-derived
peptides against cardiovascular diseases, e.g., TcNPa peptide shows
vasodilatory activity, because it activates both NPR-A and NPR-B,
showing its therapeutic potential.
The incidence of infectious and communicable diseases has increased
globally and drug resistance is becoming more frequent. Therefore, we
require more effective therapeutic agents, such as short hybrid peptides
derived from pEM-2, mastoparan-VT1 and mastoparan-B (previously
reported synthetic peptides), as well as PV and PV3 (antimicrobial ac­
tivity against gram-negative bacteria P. aeruginosa, A. baumanii,
S. aureus, and E. faecalis). Analogous peptides of stigmurin extracted
from T. stigmurus, peptides StigA6 and StigA16, showed greater anti­
bacterial activity than the original molecule against E. coli, E. cloaceae,
P. aeruginosa, S. aureus, Staphylococcus epidermidis, and E. faecalis.
Further in vitro studies are needed to understand the mechanisms
responsible for the bioactivity and cellular targets of venom-derived
peptides. In vivo experiments must identify the pharmacokinetic and
pharmacodynamic characteristics and evaluate the therapeutic potential
of venom-derived peptides in various diseases. Finally, clinical evalua­
tions are indispensable for obtaining data that corroborate the use of
synthetic peptides as new therapeutic agents. Synthetic peptides ob­
tained from animal venom continue to be an important area of research
for pharmaceutical development.
17
Biomedicine & Pharmacotherapy 170 (2024) 116015
Funding
This work was supported by the Escuela de Medicina Research Chair
which supported the Postdoc fellowship of JLDG from Tecnologico de
Monterrey, Mexico. This work was also supported by the NutriOmics y
Tecnologías Emergentes Research Chair of Tecnologico de Monterrey,
Mexico. Ms.C. scholarships for ERA and RAGM (CVU:1239208 and
CVU:1231772, respectively) were granted by CONACYT Mexico.
CRediT authorship contribution statement
Gaxiola-Muñíz Ramón Alonso: Conceptualization, Data curation,
Investigation, Visualization, Writing – original draft. Puente-Garza
César Armando: Conceptualization, Data curation, Writing – original
draft. Rivera-Aboytes Elizabeth: Data curation, Investigation, Visual­
ization, Writing – original draft. Díaz-Gómez Jorge Luis: Conceptual­
ization, Data curation, Investigation, Supervision, Visualization, Writing
– original draft, Writing – review & editing. Martín-Estal Irene:
Conceptualization, Visualization, Writing – review & editing, Writing –
original draft. García-Lara Silverio: Conceptualization, Visualization,
Writing – original draft. Castorena-Torres Fabiola: Conceptualization,
Data curation, Supervision, Writing – original draft, Writing – review &
editing.
Declaration of Generative AI and AI-assisted technologies in the
writing process
The authors declare that no AI tool was used to write or develop this
manuscript.
Declaration of Competing Interest
The authors declare that they have no competing financial interests
or personal relationships that may have influenced the work reported in
this paper.
Acknowledgments
The authors do not have any acknowledgment to give for this
manuscript.
References
[1] L. Di Renzo, P. Gualtieri, A. De Lorenzo, Diet, nutrition and chronic degenerative
diseases, Nutrients 13 (2021) 1372, https://doi.org/10.3390/nu13041372.
[2] R.E. Baker, A.S. Mahmud, I.F. Miller, M. Rajeev, F. Rasambainarivo, B.L. Rice,
S. Takahashi, A.J. Tatem, C.E. Wagner, L.-F. Wang, A. Wesolowski, C.J.E. Metcalf,
Infectious disease in an era of global change, Nat. Rev. Microbiol. 20 (2022)
193–205, https://doi.org/10.1038/s41579-021-00639-z.
[3] T.B. Smallwood, R.J. Clark, Advances in venom peptide drug discovery: where
are we at and where are we heading? Expert Opin. Drug Discov. 16 (2021)
1163–1173, https://doi.org/10.1080/17460441.2021.1922386.
[4] M.J. Page, J.E. McKenzie, P.M. Bossuyt, I. Boutron, T.C. Hoffmann, C.D. Mulrow,
L. Shamseer, J.M. Tetzlaff, E.A. Akl, S.E. Brennan, R. Chou, J. Glanville, J.
M. Grimshaw, A. Hróbjartsson, M.M. Lalu, T. Li, E.W. Loder, E. Mayo-Wilson,
S. McDonald, L.A. McGuinness, L.A. Stewart, J. Thomas, A.C. Tricco, V.A. Welch,
P. Whiting, D. Moher, The PRISMA 2020 statement: an updated guideline for
reporting systematic reviews, BMJ (2021) n71, https://doi.org/10.1136/bmj.
n71.
[5] Y.N. Utkin, C. Weise, I.E. Kasheverov, T.V. Andreeva, E.V. Kryukova, M.
N. Zhmak, V.G. Starkov, N.A. Hoang, D. Bertrand, J. Ramerstorfer, W. Sieghart,
A.J. Thompson, S.C.R. Lummis, V.I. Tsetlin, Azemiopsin from azemiops feae viper
venom, a novel polypeptide ligand of nicotinic acetylcholine receptor, J. Biol.
Chem. 287 (2012) 27079–27086, https://doi.org/10.1074/jbc.M112.363051.
[6] A. Rezaei, S. Asgari, S. Komijani, S.N. Sadat, J.-M. Sabatier, D. Nasrabadi,
K. Pooshang Bagheri, D. Shahbazzadeh, M.R. Akbari Eidgahi, M. De Waard,
H. Mirzahoseini, Discovery of leptulipin, a new anticancer protein from the
Iranian scorpion, hemiscorpius lepturus, Molecules 27 (2022) 2056, https://doi.
org/10.3390/molecules27072056.
[7] A. Lafnoune, S.-Y. Lee, J.-Y. Heo, K. Daoudi, B. Darkaoui, S. Chakir, R. Cadi,
K. Mounaji, D. Shum, H.-R. Seo, N. Oukkache, Anti-cancer activity of buthus
occitanus venom on hepatocellular carcinoma in 3D cell culture, Molecules 27
(2022) 2219, https://doi.org/10.3390/molecules27072219.
J.L. Díaz-Gómez et al.
[8] D. Aissaoui-Zid, M.-C. Saada, W. Moslah, M. Potier-Cartereau, A. Lemettre,
H. Othman, M. Gaysinski, Z. Abdelkafi-Koubaa, S. Souid, N. Marrakchi,
C. Vandier, K. Essafi-Benkhadir, N. Srairi-Abid, AaTs-1: a tetrapeptide from
androctonus australis scorpion venom, inhibiting U87 glioblastoma cells
proliferation by p53 and FPRL-1 up-regulations, Molecules 26 (2021) 7610,
https://doi.org/10.3390/molecules26247610.
[9] N. Luan, Q. Zhao, Z. Duan, M. Ji, M. Xing, T. Zhu, J. Mwangi, M. Rong, J. Liu,
R. Lai, Identification and characterization of ShSPI, a Kazal-type elastase
inhibitor from the venom of scolopendra hainanum, Toxins 11 (2019) 708,
https://doi.org/10.3390/toxins11120708.
[10] K. Conceição, G.L. de Cena, V.A. da Silva, X.A. de Oliveira Neto, V.M. de Andrade,
D.B. Tada, M. Richardson, S.A. de Andrade, S.A. Dias, M.A.R.B. Castanho,
M. Lopes-Ferreira, Design of bioactive peptides derived from CART sequence
isolated from the toadfish Thalassophryne nattereri, 3 Biotech 10 (2020), 162,
https://doi.org/10.1007/s13205-020-2151-4.
[11] D. He, Z. Cao, R. Zhang, W. Li, Molecular cloning and functional identification of
the antimicrobial peptide gene Ctri9594 from the venom of the scorpion chaerilus
tricostatus, Antibiotics 10 (2021) 896, https://doi.org/10.3390/
antibiotics10080896.
[12] X. Luo, L. Ding, X. Ye, W. Zhu, K. Zhang, F. Li, H. Jiang, Z. Zhao, Z. Chen, An
Smp43-derived short-chain α-helical peptide displays a unique sequence and
possesses antimicrobial activity against both gram-positive and gram-negative
bacteria, Toxins 13 (2021) 343, https://doi.org/10.3390/toxins13050343.
[13] F.S. Schneider, S. de Almeida Lima, G. Reis de Ávila, K.L. Castro, C. Guerra-
Duarte, E.F. Sanchez, C. Nguyen, C. Granier, F. Molina, C. Chávez-Olortegui,
Identification of protective B-cell epitopes of Atroxlysin-I: a metalloproteinase
from Bothrops atrox snake venom, Vaccine 34 (2016) 1680–1687, https://doi.
org/10.1016/j.vaccine.2016.02.035.
[14] P. Lyu, L. Ge, R. Ma, R. Wei, C.M. McCrudden, T. Chen, C. Shaw, H.F. Kwok,
Identification and pharmaceutical evaluation of novel frog skin-derived serine
proteinase inhibitor peptide–PE-BBI (Pelophylax esculentus Bowman-Birk
inhibitor) for the potential treatment of cancer, Sci. Rep. 8 (2018), 14502,
https://doi.org/10.1038/s41598-018-32947-5.
[15] T.M. Abd El-Aziz, L. Jaquillard, S. Bourgoin-Voillard, G. Martinez,
M. Triquigneaux, C. Zoukimian, S. Combemale, J.-P. Hograindleur, S. Al Khoury,
J. Escoffier, S. Michelland, P. Bulet, R. Beroud, M. Seve, C. Arnoult, M. De Waard,
Identification, characterization and synthesis of walterospermin, a sperm motility
activator from the egyptian black snake walterinnesia aegyptia venom, Int J. Mol.
Sci. 21 (2020) 7786, https://doi.org/10.3390/ijms21207786.
[16] J.K. Klint, G. Berecki, T. Durek, M. Mobli, O. Knapp, G.F. King, D.J. Adams, P.
F. Alewood, L.D. Rash, Isolation, synthesis and characterization of ω-TRTX-Cc1a,
a novel tarantula venom peptide that selectively targets L-type CaV channels,
Biochem. Pharmacol. 89 (2014) 276–286, https://doi.org/10.1016/j.
bcp.2014.02.008.
[17] K. Chionis, D. Krikorian, A.-I. Koukkou, M. Sakarellos-Daitsiotis, E. Panou-
Pomonis, Synthesis and biological activity of lipophilic analogs of the cationic
antimicrobial active peptide anoplin, J. Pept. Sci. 22 (2016) 731–736, https://
doi.org/10.1002/psc.2939.
[18] C.I. Schroeder, L.D. Rash, X. Vila-Farrés, K.J. Rosengren, M. Mobli, G.F. King, P.
F. Alewood, D.J. Craik, T. Durek, Chemical synthesis, 3D structure, and ASIC
binding site of the toxin mambalgin-2, Angew. Chem. 126 (2014) 1035–1038,
https://doi.org/10.1002/ange.201308898.
[19] H. Juichi, R. Ando, T. Ishido, M. Miyashita, Y. Nakagawa, H. Miyagawa, Chemical
synthesis of a two-domain scorpion toxin LaIT2 and its single-domain analogs to
elucidate structural factors important for insecticidal and antimicrobial activities,
J. Pept. Sci. 24 (2018), e3133, https://doi.org/10.1002/psc.3133.
[20] A. Mosbah, N. Marrakchi, P. Mansuelle, S. Kouidhi, E. Giralt, M. El Ayeb,
G. Herbette, A. Cherif, D. Gigmes, H. Darbon, K. Mabrouk, Lebetin peptides, A
new class of potent platelet aggregation inhibitors: chemical synthesis, biological
activity and NMR spectroscopic study, Int. J. Pept. Res Ther. 26 (2020) 21–31,
https://doi.org/10.1007/s10989-019-09812-8.
[21] R. de la Salud Bea, M.R. Ascuitto, L.E.L. de Johnson, Synthesis of analogs of
peptides from Buthus martensii scorpion venom with potential antibiotic activity,
Peptides 68 (2015) 228–232, https://doi.org/10.1016/j.peptides.2014.10.008.
[22] J. Giribaldi, D. Wilson, A. Nicke, Y. El Hamdaoui, G. Laconde, A. Faucherre,
H. Moha Ou Maati, N. Daly, C. Enjalbal, S. Dutertre, Synthesis, structure and
biological activity of CIA and CIB, two α-conotoxins from the predation-evoked
venom of conus catus, Toxins 10 (2018) 222, https://doi.org/10.3390/
toxins10060222.
[23] R. Luthra, S. Datta, A. Roy, Role of different peptides for cancer immunotherapy,
Int. J. Pept. Res. Ther. 27 (2021) 2777–2793, https://doi.org/10.1007/s10989-
021-10289-7.
[24] W. Yan, J. Lu, G. Li, H. Wei, W.-H. Ren, Amidated Scolopin-2 inhibits
proliferation and induces apoptosis of Hela cells in vitro and in vivo, Biotechnol.
Appl. Biochem. 65 (2018) 672–679, https://doi.org/10.1002/bab.1661.
[25] E. Jamasbi, S.S. Lucky, W. Li, M.A. Hossain, P. Gopalakrishnakone, F. Separovic,
Effect of dimerized melittin on gastric cancer cells and antibacterial activity,
Amino Acids 50 (2018) 1101–1110, https://doi.org/10.1007/s00726-018-2587-
6.
[26] C. Kim, D.S. Kim, D. Nam, S.-H. Kim, B.S. Shim, K.S. Ahn, Melittin exerts
antitumorigenic effects in human MM1.S multiple myeloma cells through the
suppression of AKT/mTOR/S6K1/4E-BP1 signaling cascades, Orient Pharm. Exp.
Med. 15 (2015) 33–44, https://doi.org/10.1007/s13596-014-0172-4.
[27] J. Sung, Y. Kim, P.F. Yu, Y. Kim, I.-H. Han, H. Bae, Subcutaneous toxicity of
melittin-dKLA in ICR mice, Mol. Cell Toxicol. 17 (2021) 417–428, https://doi.
org/10.1007/s13273-021-00148-3.
18
Biomedicine & Pharmacotherapy 170 (2024) 116015
[28] F. Mahdavi Abhari, M. Pirestani, A. Dalimi, Anti-amoebic activity of a cecropin-
melittin hybrid peptide (CM11) against trophozoites of Entamoeba histolytica,
Wien. Klin. Woche 131 (2019) 427–434, https://doi.org/10.1007/s00508-019-
01540-9.
[29] M. Moosazadeh Moghaddam, M. Eftekhary, S. Erfanimanesh, A. Hashemi,
V. Fallah Omrani, B. Farhadihosseinabadi, Z. Lasjerdi, M. Mossahebi-
Mohammadi, N. Pal Singh Chauhan, A.M. Seifalian, M. Gholipourmalekabadi,
Comparison of the antibacterial effects of a short cationic peptide and 1% silver
bioactive glass against extensively drug-resistant bacteria, pseudomonas
aeruginosa and acinetobacter baumannii, isolated from burn patients, Amino
Acids 50 (2018) 1617–1628, https://doi.org/10.1007/s00726-018-2638-z.
[30] X. Liang, K. Liu, P. Zhao, J. Zhou, F. Zhang, Y. He, H. Zhang, M.S. Fareed, Y. Lu,
Y. Xu, Z. Zhang, W. Yan, K. Wang, The effects of incorporation of the counterparts
and mimics of l-lysine on the antimicrobial activity, hemolytic activity,
cytotoxicity and tryptic stability of antimicrobial peptide polybia-MPII, Amino
Acids 54 (2022) 123–135, https://doi.org/10.1007/s00726-021-03099-0.
[31] M.D.T. Torres, A.F. Silva, G.P. Andrade, C.N. Pedron, G. Cerchiaro, A.O. Ribeiro,
V.X. Oliveira, C. Fuente-Nunez, The wasp venom antimicrobial peptide
<scp>polybia-CP</scp> and its synthetic derivatives display antiplasmodial and
anticancer properties, Bioeng. Transl. Med. 5 (2020), https://doi.org/10.1002/
btm2.10167.
[32] J. Slaninová, V. Mlsová, H. Kroupová, L. Alán, T. Tůmová, L. Monincová,
L. Borovičková, V. Fučík, V. Čeřovský, Toxicity study of antimicrobial peptides
from wild bee venom and their analogs toward mammalian normal and cancer
cells, Peptides 33 (2012) 18–26, https://doi.org/10.1016/j.
peptides.2011.11.002.
[33] M.D.T. Torres, G.P. Andrade, R.H. Sato, C.N. Pedron, T.M. Manieri, G. Cerchiaro,
A.O. Ribeiro, C. de la Fuente-Nunez, V.X. Oliveira, Natural and redesigned wasp
venom peptides with selective antitumoral activity, Beilstein J. Org. Chem. 14
(2018) 1693–1703, https://doi.org/10.3762/bjoc.14.144.
[34] A. Richardson, L. Muir, S. Mousdell, D. Sexton, S. Jones, J. Howl, K. Ross,
Modulation of mitochondrial activity in HaCaT keratinocytes by the cell
penetrating peptide Z-Gly-RGD(DPhe)-mitoparan, BMC Res. Notes 11 (2018), 82,
https://doi.org/10.1186/s13104-018-3192-1.
[35] S. Satitmanwiwat, C. Changsangfa, A. Khanuengthong, K. Promthep,
S. Roytrakul, T. Arpornsuwan, K. Saikhun, H. Sritanaudomchai, The scorpion
venom peptide BmKn2 induces apoptosis in cancerous but not in normal human
oral cells, Biomed. Pharmacother. 84 (2016) 1042–1050, https://doi.org/
10.1016/j.biopha.2016.10.041.
[36] T. Arpornsuwan, B. Buasakul, J. Jaresitthikunchai, S. Roytrakul, Potent and rapid
antigonococcal activity of the venom peptide BmKn2 and its derivatives against
different Maldi biotype of multidrug-resistant Neisseria gonorrhoeae, Peptides 53
(2014) 315–320, https://doi.org/10.1016/j.peptides.2013.10.020.
[37] C.N. Pedron, G.P. Andrade, R.H. Sato, M.D.T. Torres, G. Cerchiaro, A.O. Ribeiro,
V.X. Oliveira, Anticancer activity of VmCT1 analogs against MCF-7 cells, Chem.
Biol. Drug Des. 91 (2018) 588–596, https://doi.org/10.1111/cbdd.13123.
[38] M. Dastpeyman, P. Giacomin, D. Wilson, M.J. Nolan, P.S. Bansal, N.L. Daly, A C-
terminal fragment of chlorotoxin retains bioactivity and inhibits cell migration,
Front. Pharmacol. 10 (2019), https://doi.org/10.3389/fphar.2019.00250.
[39] S. McGonigle, U. Majumder, D. Kolber-Simonds, J. Wu, A. Hart, T. Noland,
K. TenDyke, D. Custar, D. Li, H. Du, M.H.D. Postema, W.G. Lai, N.C. Twine,
M. Woodall-Jappe, K. Nomoto, Neuropilin-1 drives tumor-specific uptake of
chlorotoxin, Cell Commun. Signal. 17 (2019), 67, https://doi.org/10.1186/
s12964-019-0368-9.
[40] A. Almaaytah, S. Tarazi, N. Mhaidat, Q. Al-Balas, T.L. Mukattash, Mauriporin, a
novel cationic α-helical peptide with selective cytotoxic activity against prostate
cancer cell lines from the venom of the scorpion androctonus mauritanicus, Int J.
Pept. Res. Ther. 19 (2013) 281–293, https://doi.org/10.1007/s10989-013-9350-
3.
[41] X.-R. Zhou, Q. Zhang, X.-B. Tian, Y.-M. Cao, Z.-Q. Liu, R. Fan, X.-F. Ding, Z. Zhu,
L. Chen, S.-Z. Luo, From a pro-apoptotic peptide to a lytic peptide: one single
residue mutation, Biochim. Et. Biophys. Acta (BBA) - Biomembr. 1858 (2016)
1914–1925, https://doi.org/10.1016/j.bbamem.2016.05.012.
[42] B.B.R. de Oliveira-Mendes, C.C.R. Horta, A.O. do Carmo, G.L. Biscoto, D.F. Sales-
Medina, H.G. Leal, P.F.P. Brandão-Dias, S.E.M. Miranda, C.J. Aguiar, V.
N. Cardoso, A.L.B. de Barros, C. Chávez-Olortégui, M.F. Leite, E. Kalapothakis,
CPP-Ts: a new intracellular calcium channel modulator and a promising tool for
drug delivery in cancer cells, Sci. Rep. 8 (2018), 14739, https://doi.org/10.1038/
s41598-018-33133-3.
[43] Q. Du, X. Hou, L. Wang, Y. Zhang, X. Xi, H. Wang, M. Zhou, J. Duan, M. Wei,
T. Chen, C. Shaw, AaeAP1 and AaeAP2: novel antimicrobial peptides from the
venom of the scorpion, androctonus aeneas: structural characterisation,
molecular cloning of biosynthetic precursor-encoding cDNAs and engineering of
analogues with enhanced antimicrobial and anticancer activities, Toxins 7 (2015)
219–237, https://doi.org/10.3390/toxins7020219.
[44] J. Krämer, T. Lüddecke, M. Marner, E. Maiworm, J. Eichberg, K. Hardes, T.
F. Schäberle, A. Vilcinskas, R. Predel, Antimicrobial, insecticidal and cytotoxic
activity of linear venom peptides from the pseudoscorpion chelifer cancroides,
Toxins 14 (2022) 58, https://doi.org/10.3390/toxins14010058.
[45] W. Moslah, D. Aissaoui-Zid, S. Aboudou, Z. Abdelkafi-Koubaa, M. Potier-
Cartereau, A. Lemettre, I. ELBini-Dhouib, N. Marrakchi, D. Gigmes, C. Vandier,
J. Luis, K. Mabrouk, N. Srairi-Abid, Strengthening anti-glioblastoma effect by
multi-branched dendrimers design of a scorpion venom tetrapeptide, Molecules
27 (2022) 806, https://doi.org/10.3390/molecules27030806.
J.L. Díaz-Gómez et al.
[46] Z. Setayesh-Mehr, A. Asoodeh, Biochemical characterization of HL-7 and HL-10
peptides identified from scorpion venom of hemiscorpius lepturus, Int. J. Pept.
Res. Ther. 24 (2018) 421–430, https://doi.org/10.1007/s10989-017-9625-1.
[47] B. Li, P. Lyu, X. Xi, L. Ge, R. Mahadevappa, C. Shaw, H.F. Kwok, Triggering of
cancer cell cycle arrest by a novel scorpion venom-derived
peptide—Gonearrestide, J. Cell Mol. Med. 22 (2018) 4460–4473, https://doi.org/
10.1111/jcmm.13745.
[48] M.S. Peña-Carrillo, E.A. Pinos-Tamayo, B. Mendes, C. Domínguez-Borbor,
C. Proaño-Bolaños, D.C. Miguel, J.R. Almeida, Dissection of phospholipases A2
reveals multifaceted peptides targeting cancer cells, Leishmania and bacteria,
Bioorg. Chem. 114 (2021), 105041, https://doi.org/10.1016/j.
bioorg.2021.105041.
[49] C. Xu, Y. Wang, Q. Tu, Z. Zhang, M. Chen, J. Mwangi, Y. Li, Y. Jin, X. Zhao, R. Lai,
Targeting surface nucleolin induces autophagy-dependent cell death in pancreatic
cancer via AMPK activation, Oncogene 38 (2019) 1832–1844, https://doi.org/
10.1038/s41388-018-0556-x.
[50] P. Zhang, Y. Yan, J. Wang, X. Dong, G. Zhang, Y. Zeng, Z. Liu, An anti-cancer
peptide LVTX-8 inhibits the proliferation and migration of lung tumor cells by
regulating causal genes’ expression in p53-related pathways, Toxins 12 (2020)
367, https://doi.org/10.3390/toxins12060367.
[51] F. Li, S. Wu, N. Chen, J. Zhu, X. Zhao, P. Zhang, Y. Zeng, Z. Liu, Fatty acid
modification of the anticancer peptide LVTX-9 to enhance its cytotoxicity against
malignant melanoma cells, Toxins 13 (2021) 867, https://doi.org/10.3390/
toxins13120867.
[52] R.O. Araújo, M.L. Leite, T.T.B. Dutra, N. Brito da Cunha, T.M.B. Rezende, M.H.
S. Ramada, S.C. Dias, Evaluation of the biotechnological potential of peptide
Cupiennin 1a and analogs, Front. Microbiol. 13 (2022), https://doi.org/10.3389/
fmicb.2022.850007.
[53] L.F.R.N. de Moraes, P.S. e Silva, T.C.P.L. Pereira, T.A. Almeida Rodrigues, B.
E. Farias Frihling, R.A. da Costa, H.F.V. Torquato, C.S. Lima, E.J. Paredes-
Gamero, L. Migliolo, First generation of multifunctional peptides derived from
latarcin-3a from Lachesana tarabaevi spider toxin, Front. Microbiol. 13 (2022),
https://doi.org/10.3389/fmicb.2022.965621.
[54] M.A.L. Abdel-Salam, B. Pinto, G. Cassali, L. Bueno, G. Pêgas, F. Oliveira, I. Silva,
A. Klein, E.M. de Souza-Fagundes, M.E. de Lima, J. Carvalho-Tavares, LyeTx I-b
peptide attenuates tumor burden and metastasis in a mouse 4T1 breast cancer
model, Antibiotics 10 (2021) 1136, https://doi.org/10.3390/
antibiotics10091136.
[55] C.N. da Silva, L.F.N. Dourado, L.M. Silva, A.B. de Lima, M.E. de Lima, A. Silva-
Cunha, S.L. Fialho, Pathophysiological effects of lycosa erythrognatha derived
peptide LyeTxI-b on RKO-AS-45-1 colorectal carcinoma cell line using the chicken
chorioallantoic membrane model, Int. J. Pept. Res. Ther. 28 (2022), 36, https://
doi.org/10.1007/s10989-021-10349-y.
[56] S.J. Moore, C.L. Leung, H.K. Norton, J.R. Cochran, Engineering agatoxin, a
cystine-knot peptide from spider venom, as a molecular probe for in vivo tumor
imaging, PLOS One 8 (2013), e60498, https://doi.org/10.1371/journal.
pone.0060498.
[57] A. Kumari, S. Ameri, P. Ravikrishna, A. Dhayalan, S. Kamala-Kannan,
T. Selvankumar, M. Govarthanan, Isolation and characterization of conotoxin
protein from conus inscriptus and its potential anticancer activity against cervical
cancer (HeLa-HPV 16 associated) cell lines, Int. J. Pept. Res. Ther. 26 (2020)
1051–1059, https://doi.org/10.1007/s10989-019-09907-2.
[58] P. Anand, P. Filipenko, J. Huaman, M. Lyudmer, M. Hossain, C. Santamaria,
K. Huang, O.O. Ogunwobi, M. Holford, Selective inhibition of liver cancer cells
using venom peptide, Mar. Drugs 17 (2019) 587, https://doi.org/10.3390/
md17100587.
[59] K.A. Elnahriry, D.C.C. Wai, B. Krishnarjuna, N.N. Badawy, B. Chittoor, C.
A. MacRaild, B.J. Williams-Noonan, J.M. Surm, D.K. Chalmers, A.H. Zhang,
S. Peigneur, M. Mobli, J. Tytgat, P. Prentis, R.S. Norton, Structural and functional
characterisation of a novel peptide from the Australian sea anemone Actinia
tenebrosa, Toxicon 168 (2019) 104–112, https://doi.org/10.1016/j.
toxicon.2019.07.002.
[60] C.V. Bowen, D. DeBay, H.S. Ewart, P. Gallant, S. Gormley, T.T. Ilenchuk, U. Iqbal,
T. Lutes, M. Martina, G. Mealing, N. Merkley, S. Sperker, M.J. Moreno, C. Rice, R.
T. Syvitski, J.M. Stewart, In vivo detection of human TRPV6-rich tumors with
anti-cancer peptides derived from soricidin, PLOS One 8 (2013), e58866, https://
doi.org/10.1371/journal.pone.0058866.
[61] B. Tourki, A. Dumesnil, E. Belaidi, S. Ghrir, D. Godin-Ribuot, N. Marrakchi,
V. Richard, P. Mulder, E. Messadi, Lebetin 2, a snake venom-derived b-type
natriuretic peptide, provides immediate and prolonged protection against
myocardial ischemia-reperfusion injury via modulation of post-ischemic
inflammatory response, Toxins 11 (2019) 524, https://doi.org/10.3390/
toxins11090524.
[62] B. Duzzi, C.C.F. Silva, R.T. Kodama, D. Cajado-Carvalho, C.C. Squaiella-Baptistão,
F.C.V. Portaro, New insights into the hypotensins from tityus serrulatus venom:
pro-inflammatory and vasopeptidases modulation activities, Toxins 13 (2021)
846, https://doi.org/10.3390/toxins13120846.
[63] R.T. Kodama, D. Cajado-Carvalho, A.K. Kuniyoshi, E.S. Kitano, A.K. Tashima, B.
F. Barna, A.C. Takakura, S.M.T. Serrano, W. Dias-Da-Silva, D.V. Tambourgi, F.
V. Portaro, New proline-rich oligopeptides from the venom of African adders:
insights into the hypotensive effect of the venoms, Biochim. Biophys. Acta (BBA) -
Gen. Subj. 1850 (2015) 1180–1187, https://doi.org/10.1016/j.
bbagen.2015.02.005.
[64] E.L. Pinheiro-Júnior, J. Boldrini-França, L.M.P. de Campos Araújo, N.A. Santos-
Filho, L.M. Bendhack, E.M. Cilli, E.C. Arantes, LmrBPP9: A synthetic bradykinin-
potentiating peptide from Lachesis muta rhombeata venom that inhibits the
19
Biomedicine & Pharmacotherapy 170 (2024) 116015
angiotensin-converting enzyme activity in vitro and reduces the blood pressure of
hypertensive rats, Peptides 102 (2018) 1–7, https://doi.org/10.1016/j.
peptides.2018.01.015.
[65] R.S. Aires, L.D. Vieira, A.C.N. Freitas, M.E. de Lima, N.K.S. Lima, J.S. Farias, A.
D. Paixão, NO mediates the effect of the synthetic natriuretic peptide NPCdc on
kidney and aorta in nephrectomised rats, Eur. J. Pharmacol. 866 (2020), 172780,
https://doi.org/10.1016/j.ejphar.2019.172780.
[66] R.S. Aires, L. Francisco da Silva Filho, L.F. Gomes Rebello Ferreira, M.
Z. Hernandes, M.F. Machado Marcondes, A.K. Carmona, A.D. Oliveira da Paixão,
L.D. Vieira, NPCdc, a synthetic natriuretic peptide, is a substrate to neprilysin and
enhances blood pressure-lowering induced by enalapril in 5/6 nephrectomized
rats, Toxicon 203 (2021) 30–39, https://doi.org/10.1016/j.toxicon.2021.09.016.
[67] T. Reeks, A. Jones, A. Brust, S. Sridharan, L. Corcilius, B.L. Wilkinson,
M. Thaysen-Andersen, R.J. Payne, R.M. Kini, N.L. Daly, P.F. Alewood, A, Defined
α-helix in the bifunctional O -glycosylated natriuretic peptide TcNPa from the
venom of tropidechis carinatus, Angew. Chem. 127 (2015) 4910–4913, https://
doi.org/10.1002/ange.201411914.
[68] Z. Setayesh-Mehr, L.V. Ghasemi, A. Asoodeh, Evaluation of the in vivo
antihypertensive effect and antioxidant activity of HL-7 and HL-10 peptide in
mice, Mol. Biol. Rep. 48 (2021) 5571–5578, https://doi.org/10.1007/s11033-
021-06576-7.
[69] B.L. Furman, The development of Byetta (exenatide) from the venom of the Gila
monster as an anti-diabetic agent, Toxicon 59 (2012) 464–471, https://doi.org/
10.1016/j.toxicon.2010.12.016.
[70] P.H. Lugo-Fabres, L.M. Otero-Sastre, J. Bernáldez-Sarabia, T.A. Camacho-
Villegas, N. Sánchez-Campos, J. Serrano-Bello, L.A. Medina, S. Muñiz-Hernández,
L. de la Cruz, I. Arenas, A. Barajas-Martínez, D.E. Garcia, L. Nuñez-Garcia,
J. González-Canudas, A.F. Licea-Navarro, Potential therapeutic applications of
synthetic conotoxin s-cal14.2b, derived from californiconus californicus, for
treating type 2 diabetes, Biomedicines 9 (2021) 936, https://doi.org/10.3390/
biomedicines9080936.
[71] S.A. Ali, M. Alam, A. Abbasi, H. Kalbacher, T.J. Schaechinger, Y. Hu, C. Zhijian,
W. Li, W. Voelter, Structure–activity relationship of a highly selective peptidyl
inhibitor of Kv1.3 voltage-gated K+-channel from scorpion (B. sindicus) venom,
Int. J. Pept. Res. Ther. 20 (2014) 19–32, https://doi.org/10.1007/s10989-013-
9362-z.
[72] Y.A. Palikova, V.A. Palikov, I.A. Dyachenko, Maximum tolerant dose and
analgesic activity of PT1 peptide, Res. Results Pharmacol. 5 (2019) 37–42,
https://doi.org/10.3897/rrpharmacology.5.38520.
[73] S.R. Sousa, J.S. Wingerd, A. Brust, C. Bladen, L. Ragnarsson, V. Herzig, J.R. Deuis,
S. Dutertre, I. Vetter, G.W. Zamponi, G.F. King, P.F. Alewood, R.J. Lewis,
Discovery and mode of action of a novel analgesic β-toxin from the African spider
Ceratogyrus darlingi, PLOS One 12 (2017), e0182848, https://doi.org/10.1371/
journal.pone.0182848.
[74] Gonçalves Lesport, Kuylle Stura, Ciolek Mourier, Servent Bourinet, Benoit Gilles,
Evaluation of the spider (Phlogiellus genus) phlotoxin 1 and synthetic variants as
antinociceptive drug candidates, Toxins 11 (2019) 484, https://doi.org/10.3390/
toxins11090484.
[75] F.C. Cardoso, Z. Dekan, J.J. Smith, J.R. Deuis, I. Vetter, V. Herzig, P.F. Alewood,
G.F. King, R.J. Lewis, Modulatory features of the novel spider toxin μ-TRTX-Df1a
isolated from the venom of the spider Davus fasciatus, Br. J. Pharmacol. 174
(2017) 2528–2544, https://doi.org/10.1111/bph.13865.
[76] I.-W. Hwang, M.K. Shin, Y.-J. Lee, S.T. Kim, S.Y. Lee, B. Lee, W. Jang, J.-H. Yeo,
S. Lee, J.-S. Sung, N-type Cav channel inhibition by spider venom peptide of
Argiope bruennichi, Mol. Cell Toxicol. 17 (2021) 59–67, https://doi.org/
10.1007/s13273-020-00109-2.
[77] V. Herzig, Y.-C. Chen, Y.K.-Y. Chin, Z. Dekan, Y.-W. Chang, H.-M. Yu, P.
F. Alewood, C.-C. Chen, G.F. King, The tarantula toxin ω-Avsp1a specifically
inhibits human CaV3.1 and CaV3.3 via the extracellular S3-S4 loop of the domain
1 voltage-sensor, Biomedicines 10 (2022) 1066, https://doi.org/10.3390/
biomedicines10051066.
[78] B.D. Moyer, J.K. Murray, J. Ligutti, K. Andrews, P. Favreau, J.B. Jordan, J.H. Lee,
D. Liu, J. Long, K. Sham, L. Shi, R. Stöcklin, B. Wu, R. Yin, V. Yu, A. Zou,
K. Biswas, L.P. Miranda, Pharmacological characterization of potent and selective
NaV1.7 inhibitors engineered from Chilobrachys jingzhao tarantula venom
peptide JzTx-V, PLOS One 13 (2018), e0196791, https://doi.org/10.1371/
journal.pone.0196791.
[79] A.C.N. Freitas, G.C. Silva, D.F. Pacheco, A.M.C. Pimenta, V.S. Lemos, I.D.
G. Duarte, M.E. de Lima, The synthetic peptide PnPP-19 induces peripheral
antinociception via activation of NO/cGMP/KATP pathway: Role of eNOS and
nNOS, Nitric Oxide 64 (2017) 31–38, https://doi.org/10.1016/j.
niox.2017.01.004.
[80] D. da Fonseca Pacheco, A.C.N. Freitas, A.M.C. Pimenta, I.D.G. Duarte, M.E. de
Lima, A spider derived peptide, PnPP-19, induces central antinociception
mediated by opioid and cannabinoid systems, J. Venom. Anim. Toxins Incl. Trop.
Dis. 22 (2016), 34, https://doi.org/10.1186/s40409-016-0091-6.
[81] A. Freitas, S. Peigneur, F. Macedo, J. Menezes-Filho, P. Millns, L. Medeiros,
M. Arruda, J. Cruz, N. Holliday, J. Tytgat, G. Hathway, M. de Lima, The peptide
PnPP-19, a spider toxin derivative, activates μ-opioid receptors and modulates
calcium channels, Toxins 10 (2018) 43, https://doi.org/10.3390/
toxins10010043.
[82] S. Bagheri-Ziari, D. Shahbazzadeh, S. Sardari, J.-M. Sabatier, K. Pooshang
Bagheri, Discovery of a new analgesic peptide, leptucin, from the Iranian
scorpion, hemiscorpius lepturus, Molecules 26 (2021) 2580, https://doi.org/
10.3390/molecules26092580.
J.L. Díaz-Gómez et al.
[83] X. Liu, G. Yao, K. Wang, Y. Liu, X. Wan, H. Jiang, Structural and functional
characterization of conotoxins from conus achatinus targeting NMDAR, Mar.
Drugs 18 (2020) 135, https://doi.org/10.3390/md18030135.
[84] S. Peigneur, M. Paolini-Bertrand, H. Gaertner, D. Biass, A. Violette, R. Stöcklin,
P. Favreau, J. Tytgat, O. Hartley, δ-conotoxins synthesized using an acid-
cleavable solubility tag approach reveal key structural determinants for NaV
subtype selectivity, J. Biol. Chem. 289 (2014) 35341–35350, https://doi.org/
10.1074/jbc.M114.610436.
[85] H. Arcuri, P. Gomes, B. de Souza, N. Dias, P. Brigatte, R. Stabeli, M. Palma,
Paulistine—the functional duality of a wasp venom peptide toxin, Toxins 8
(2016) 61, https://doi.org/10.3390/toxins8030061.
[86] N. Wang, Y. Huang, A. Li, H. Jiang, J. Wang, J. Li, L. Qiu, K. Li, Y. Lu,
Hydrostatin-TL1, an anti-inflammatory active peptide from the venom gland of
hydrophis cyanocinctus in the South China Sea, Int. J. Mol. Sci. 17 (2016) 1940,
https://doi.org/10.3390/ijms17111940.
[87] A. Csoti, R. del Carmen Nájera Meza, F. Bogár, G. Tajti, T.G. Szanto, Z. Varga, G.
B. Gurrola, G.K. Tóth, L.D. Possani, G. Panyi, sVmKTx, a transcriptome analysis-
based synthetic peptide analogue of Vm24, inhibits Kv1.3 channels of human T
cells with improved selectivity, Biochem Pharmacol. 199 (2022), 115023,
https://doi.org/10.1016/j.bcp.2022.115023.
[88] E.N. Komegae, T.A.M. Souza, L.Z. Grund, C. Lima, M. Lopes-Ferreira, Multiple
functional therapeutic effects of TnP: a small stable synthetic peptide derived
from fish venom in a mouse model of multiple sclerosis, PLOS One 12 (2017),
e0171796, https://doi.org/10.1371/journal.pone.0171796.
[89] A. Franco, S.N. Kompella, K.B. Akondi, C. Melaun, N.L. Daly, C.W. Luetje, P.
F. Alewood, D.J. Craik, D.J. Adams, F. Marí, RegIIA: An α4/7-conotoxin from the
venom of Conus regius that potently blocks α3β4 nAChRs, Biochem. Pharmacol.
83 (2012) 419–426, https://doi.org/10.1016/j.bcp.2011.11.006.
[90] S. Peigneur, P. Devi, A. Seldeslachts, S. Ravichandran, L. Quinton, J. Tytgat,
Structure-function elucidation of a new α-conotoxin, MilIA, from conus
milneedwardsi, Mar. Drugs 17 (2019) 535, https://doi.org/10.3390/
md17090535.
[91] F. Fisher, Y. Zhang, P.F.Y. Vincent, J. Gajewiak, T.J. Gordon, E. Glowatzki, P.
A. Fuchs, J.M. McIntosh, Cy3-RgIA-5727 labels and inhibits α9-containing
nAChRs of cochlear hair cells, Front. Cell Neurosci. 15 (2021), https://doi.org/
10.3389/fncel.2021.697560.
[92] Y. Ma, Q. Cao, M. Yang, Y. Gao, S. Fu, W. Du, D.J. Adams, T. Jiang, H.-S. Tae,
R. Yu, Single-disulfide conopeptide Czon1107, an allosteric antagonist of the
human α3β4 nicotinic acetylcholine receptor, Mar. Drugs 20 (2022) 497, https://
doi.org/10.3390/md20080497.
[93] E.V. Kryukova, N.S. Egorova, D.S. Kudryavtsev, D.S. Lebedev, E.N. Spirova, M.
N. Zhmak, A.I. Garifulina, I.E. Kasheverov, Y.N. Utkin, V.I. Tsetlin, From
synthetic fragments of endogenous three-finger proteins to potential drugs, Front.
Pharmacol. 10 (2019), https://doi.org/10.3389/fphar.2019.00748.
[94] I. Shelukhina, M. Zhmak, A. Lobanov, I. Ivanov, A. Garifulina, I. Kravchenko,
E. Rasskazova, M. Salmova, E. Tukhovskaya, V. Rykov, G. Slashcheva,
N. Egorova, I. Muzyka, V. Tsetlin, Y. Utkin, Azemiopsin, a selective peptide
antagonist of muscle nicotinic acetylcholine receptor: preclinical evaluation as a
local muscle relaxant, Toxins 10 (2018) 34, https://doi.org/10.3390/
toxins10010034.
[95] X. Zhang, D. Tu, S. Li, N. Li, D. Li, Y. Gao, L. Tian, J. Liu, X. Zhang, J.-S. Hong,
L. Hou, J. Zhao, Q. Wang, A novel synthetic peptide SVHRSP attenuates
dopaminergic neurodegeneration by inhibiting NADPH oxidase-mediated
neuroinflammation in experimental models of Parkinson’s disease, Free Radic.
Biol. Med. 188 (2022) 363–374, https://doi.org/10.1016/j.
freeradbiomed.2022.06.241.
[96] J. Ciolek, C. Zoukimian, J. Dhot, M. Burban, M. Triquigneaux, B. Lauzier,
C. Guimbert, D. Boturyn, M. Ferron, L. Ciccone, L. Tepshi, E. Stura, P. Legrand,
P. Robin, G. Mourier, B. Schaack, I. Fellah, G. Blanchet, C. Gauthier-Erfanian,
R. Beroud, D. Servent, M. De Waard, N. Gilles, MT9, a natural peptide from black
mamba venom antagonizes the muscarinic type 2 receptor and reverses the M2R-
agonist-induced relaxation in rat and human arteries, Biomed. Pharmacother. 150
(2022), 113094, https://doi.org/10.1016/j.biopha.2022.113094.
[97] J. Luo, Y. Zhang, M. Gong, S. Lu, Y. Ma, X. Zeng, S. Liang, Molecular surface of
JZTX-V (β-Theraphotoxin-Cj2a) interacting with voltage-gated sodium channel
subtype NaV1.4, Toxins 6 (2014) 2177–2193, https://doi.org/10.3390/
toxins6072177.
[98] S. Kunda, Y. Yuan, R.D. Balsara, J. Zajicek, F.J. Castellino, Hydroxyproline-
induced helical disruption in conantokin Rl-B affects subunit-selective
antagonistic activities toward ion channels of N-methyl-d-aspartate receptors,
J. Biol. Chem. 290 (2015) 18156–18172, https://doi.org/10.1074/jbc.
M115.650341.
[99] X. Li, X. Wu, N. Li, D. Li, A. Sui, K. Khan, B. Ge, S. Li, S. Li, J. Zhao, Scorpion
venom heat-resistant synthesized peptide ameliorates 6-OHDA-induced
neurotoxicity and neuroinflammation: likely role of Nav1.6 inhibition in
microglia, Br. J. Pharmacol. 178 (2021) 3553–3569, https://doi.org/10.1111/
bph.15502.
[100] S.Y. Guo, R.X. Guan, X.D. Chi, Yue-Zhang, A.R. Sui, W. Zhao, K. Supratik, J.
Y. Yang, J. Zhao, S. Li, Scorpion venom heat-resistant synthetic peptide protects
dopamine neurons against 6-hydroxydopamine neurotoxicity in C. elegans, Brain
Res. Bull. 190 (2022) 195–203, https://doi.org/10.1016/j.
brainresbull.2022.09.022.
[101] C.P. Bernardes, N.A.G. Santos, T.R. Costa, F. Sisti, L. Amaral, D.L. Menaldo, M.
K. Amstalden, D.L. Ribeiro, L.M.G. Antunes, S.V. Sampaio, A.C. Santos,
A synthetic snake-venom-based tripeptide protects PC12 cells from the
neurotoxicity of acrolein by improving axonal plasticity and bioenergetics,
20
Biomedicine & Pharmacotherapy 170 (2024) 116015
Neurotox. Res. 37 (2020) 227–237, https://doi.org/10.1007/s12640-019-00111-
0.
[102] P. Bhattacharjee, D. Bhattacharyya, Factor V activator from daboia russelli
russelli venom destabilizes β-amyloid aggregate, the hallmark of Alzheimer
disease, J. Biol. Chem. 288 (2013) 30559–30570, https://doi.org/10.1074/jbc.
M113.511410.
[103] L.C. Camargo, L.G. Veras, G. Vaz, A.C.B. de Souza, M.R. Mortari, Octovespin, a
peptide bioinspired by wasp venom, prevents cognitive deficits induced by
amyloid-β in Alzheimer’s disease mouse model, Neuropeptides 93 (2022),
102233, https://doi.org/10.1016/j.npep.2022.102233.
[104] X. Xu, H. Xu, F. Ren, L. Huang, J. Xu, F. Li, Protective effect of scorpion venom
heat-resistant synthetic peptide against PM2.5-induced microglial polarization
via TLR4-mediated autophagy activating PI3K/AKT/NF-κB signaling pathway,
J. Neuroimmunol. 355 (2021), 577567, https://doi.org/10.1016/j.
jneuroim.2021.577567.
[105] C. Alberto-Silva, F.C. Vieira Portaro, R.T. Kodama, H.Q. Pantaleão, H. Inagaki,
K. Nihei, K. Konno, Comprehensive analysis and biological characterization of
venom components from solitary scoliid wasp campsomeriella annulata annulata,
Toxins 13 (2021) 885, https://doi.org/10.3390/toxins13120885.
[106] M. Okada, I. Kozaki, H. Honda, Antidepressive effect of an inward rectifier K+
channel blocker peptide, tertiapin-RQ, PLOS One 15 (2020), e0233815, https://
doi.org/10.1371/journal.pone.0233815.
[107] H. Memariani, D. Shahbazzadeh, R. Ranjbar, M. Behdani, M. Memariani,
K. Pooshang Bagheri, Design and characterization of short hybrid antimicrobial
peptides from pEM-2, mastoparan-VT1, and mastoparan-B, Chem. Biol. Drug Des.
89 (2017) 327–338, https://doi.org/10.1111/cbdd.12864.
[108] Y. Kim, M. Son, E.-Y. Noh, S. Kim, C. Kim, J.-H. Yeo, C. Park, K. Lee, W. Bang, MP-
V1 from the venom of social wasp vespula vulgaris is a de novo type of
mastoparan that displays superior antimicrobial activities, Molecules 21 (2016)
512, https://doi.org/10.3390/molecules21040512.
[109] Y. Lv, J. Wang, H. Gao, Z. Wang, N. Dong, Q. Ma, A. Shan, Antimicrobial
properties and membrane-active mechanism of a potential α-helical antimicrobial
derived from cathelicidin PMAP-36, PLOS One 9 (2014), e86364, https://doi.org/
10.1371/journal.pone.0086364.
[110] A. Parente, A. Daniele-Silva, A. Furtado, M. Melo, A. Lacerda, M. Queiroz,
C. Moreno, E. Santos, H. Rocha, E. Barbosa, E. Carvalho, A. Silva-Júnior, M. Silva,
M. Fernandes-Pedrosa, Analogs of the scorpion venom peptide stigmurin:
structural assessment, toxicity, and increased antimicrobial activity, Toxins 10
(2018) 161, https://doi.org/10.3390/toxins10040161.
[111] J. Park, J.H. Oh, H.K. Kang, M.-C. Choi, C.H. Seo, Y. Park, Scorpion-venom-
derived antimicrobial peptide Css54 exerts potent antimicrobial activity by
disrupting bacterial membrane of zoonotic bacteria, Antibiotics 9 (2020) 831,
https://doi.org/10.3390/antibiotics9110831.
[112] J. Jalaei, S. Layeghi-Ghalehsoukhteh, A. Hosseini, M. Fazeli, Antibacterial effects
of gold nanoparticles functionalized with the extracted peptide from Vespa
orientalis wasp venom, J. Pept. Sci. 24 (2018), e3124, https://doi.org/10.1002/
psc.3124.
[113] C. Cesa-Luna, J. Muñoz-Rojas, G. Saab-Rincon, A. Baez, Y.E. Morales-García, V.
R. Juárez-González, V. Quintero-Hernández, Structural characterization of
scorpion peptides and their bactericidal activity against clinical isolates of
multidrug-resistant bacteria, PLOS One 14 (2019), e0222438, https://doi.org/
10.1371/journal.pone.0222438.
[114] R. de la Salud Bea, L.J. North, S. Horiuchi, E.R. Frawley, Q. Shen, Antimicrobial
activity and toxicity of analogs of wasp venom EMP peptides. Potential influence
of oxidized methionine, Antibiotics 10 (2021) 1208, https://doi.org/10.3390/
antibiotics10101208.
[115] M.L. Monteiro, D.B. Lima, K.A. Freire, C. Nicolaski Pedron, E.P. Magalhães, B.
P. Silva, A.B. García-Jareño, C.S. De Oliveira, J.V.S. Nunes, M.M. Marinho, R.R.P.
P.B. de Menezes, M. Orzaéz, V.X. Oliveira Junior, A.M.C. Martins, Rational design
of a trypanocidal peptide derived from Dinoponera quadriceps venom, Eur. J.
Med Chem. 241 (2022), 114624, https://doi.org/10.1016/j.
ejmech.2022.114624.
[116] R. dos S. Cunha Neto, H. Vigerelli, C. Jared, M.M. Antoniazzi, L.B. Chaves, A. de
C.R. da Silva, R.L. de Melo, J.M. Sciani, D.C. Pimenta, Synergic effects between
ocellatin-F1 and bufotenine on the inhibition of BHK-21 cellular infection by the
rabies virus, J. Venom. Anim. Toxins Incl. Trop. Dis. 21 (2015), 50, https://doi.
org/10.1186/s40409-015-0048-1.
[117] M. Xing, M. Ji, J. Hu, T. Zhu, Y. Chen, X. Bai, J. Mwangi, G. Mo, R. Lai, L. Jin,
Snake cathelicidin derived peptide inhibits zika virus infection, Front. Microbiol.
11 (2020), https://doi.org/10.3389/fmicb.2020.01871.
[118] J. Park, H. Kim, H.-K. Kang, M.-C. Choi, Y. Park, Lycosin-II exhibits antifungal
activity and inhibits dual-species biofilm by candida albicans and staphylococcus
aureus, J. Fungi 8 (2022) 901, https://doi.org/10.3390/jof8090901.
[119] K. Wang, F. Jia, W. Dang, Y. Zhao, R. Zhu, M. Sun, S. Qiu, X. An, Z. Ma, Y. Zhu,
J. Yan, Z. Kong, W. Yan, R. Wang, Antifungal effect and action mechanism of
antimicrobial peptide polybia-CP, J. Pept. Sci. 22 (2016) 28–35, https://doi.org/
10.1002/psc.2835.
[120] S.S. Snyder, J.W. Gleaton, D. Kirui, W. Chen, N.J. Millenbaugh, Antifungal
activity of synthetic scorpion venom-derived peptide analogues against candida
albicans, Int. J. Pept. Res. Ther. 27 (2021) 281–291, https://doi.org/10.1007/
s10989-020-10084-w.
[121] F. Guilhelmelli, N. Vilela, K.S. Smidt, M.A. de Oliveira, A. da Cunha Morales
Álvares, M.C.L. Rigonatto, P.H. da Silva Costa, A.H. Tavares, S.M. de Freitas, A.
M. Nicola, O.L. Franco, L. da, S. Derengowski, E.F. Schwartz, M.R. Mortari, A.
L. Bocca, P. Albuquerque, I. Silva-Pereira, Activity of scorpion venom-derived
antifungal peptides against planktonic cells of candida spp. and cryptococcus
J.L. Díaz-Gómez et al.
neoformans and candida albicans biofilms, Front. Microbiol. 7 (2016), https://
doi.org/10.3389/fmicb.2016.01844.
[122] C. Song, R. Wen, J. Zhou, X. Zeng, Z. Kou, J. Zhang, T. Wang, P. Chang, Y. Lv,
R. Wu, Antibacterial and antifungal properties of a novel antimicrobial peptide
GK-19 and its application in skin and soft tissue infections induced by MRSA or
candida albicans, Pharmaceutics 14 (2022) 1937, https://doi.org/10.3390/
pharmaceutics14091937.
[123] M. Memariani, H. Memariani, Z. Poursafavi, Z. Baseri, Anti-fungal effects and
mechanisms of action of wasp venom-derived peptide mastoparan-VT1 against
candida albicans, Int. J. Pept. Res. Ther. 28 (2022), 96, https://doi.org/10.1007/
s10989-022-10401-5.
[124] Y. Liu, Y. Tang, X. Tang, M. Wu, S. Hou, X. Liu, J. Li, M. Deng, S. Huang, L. Jiang,
Anti-toxoplasma gondii effects of a novel spider peptide XYP1 in vitro and in vivo,
Biomedicines 9 (2021) 934, https://doi.org/10.3390/biomedicines9080934.
[125] D.R.R. de Assis, P.M. de, O. Pimentel, P.V.M. dos Reis, R.A.N. Rabelo, R.W.
A. Vitor, M. do N. Cordeiro, L.F. Felicori, C.D.C. Olórtegui, J.M. Resende, M.
M. Teixeira, M.H. Borges, M.E. de Lima, A.M. de, C. Pimenta, F.S. Machado,
Tityus serrulatus (Scorpion): from the crude venom to the construction of
synthetic peptides and their possible therapeutic application against toxoplasma
gondii infection, Front. Cell Infect. Microbiol. 11 (2021), https://doi.org/
10.3389/fcimb.2021.706618.
[126] E. Kordestani Shargh, M. Pirestani, J. Sadraei, In vitro toxicity evaluation of short
cationic antimicrobial peptide (CM11) on Blastocystis sp, Acta Trop. 204 (2020),
105384, https://doi.org/10.1016/j.actatropica.2020.105384.
[127] S. khalili, E. Ebrahimzade, M. Mohebali, P. Shayan, S. Mohammadi-Yeganeh,
M. Moosazadeh Moghaddam, S. Elikaee, B. Akhoundi, M.K. Sharifi-Yazdi,
Investigation of the antimicrobial activity of a short cationic peptide against
promastigote and amastigote forms of Leishmania major (MHRO/IR/75/ER): an
in vitro study, Exp. Parasitol. 196 (2019) 48–54, https://doi.org/10.1016/j.
exppara.2018.11.006.
[128] G. Aqeele, P. Shayan, E. Ebrahimzade Abkooh, M. Mohebali, Evaluation of
curcumin and CM11 peptide alone and in combination against amastigote form of
Iranian strain of L. major (MRHO/IR75/ER) in vitro, Exp. Parasitol. 229 (2021),
108151, https://doi.org/10.1016/j.exppara.2021.108151.
[129] K. Yee, M. Pitts, P. Tongyoo, P. Rojnuckarin, M. Wilkinson, Snake venom
metalloproteinases and their peptide inhibitors from Myanmar Russell’s viper
venom, Toxins 9 (2016) 15, https://doi.org/10.3390/toxins9010015.
[130] S.G. De-Simone, P. Napoleão-Pego, L.A.L. Teixeira-Pinto, J.D.L. Santos, T.S. De-
Simone, A.R. Melgarejo, A.S. Aguiar, D.P. Marchi-Salvador, Linear B-cell epitopes
in BthTX-1, BthTX-II and BthA-1, phospholipase A2′s from Bothrops jararacussu
snake venom, recognized by therapeutically neutralizing commercial horse
antivenom, Toxicon 72 (2013) 90–101, https://doi.org/10.1016/j.
toxicon.2013.06.004.
[131] P. D. Vaz de Melo, S. de Almeida Lima, P. Araújo, R. Medina Santos, E. Gonzalez,
A. Alves Belo, R.A. Machado-de-Ávila, F. Costal-Oliveira, V. T. Soccol, C. Guerra-
Duarte, L. Rezende, C. Chavez-Olortegui, Immunoprotection against lethal effects
of Crotalus durissus snake venom elicited by synthetic epitopes trapped in
liposomes, Int. J. Biol. Macromol. 161 (2020) 299–307, https://doi.org/10.1016/
j.ijbiomac.2020.05.171.
[132] G. Martinez, J.-P. Hograindleur, S. Voisin, R. Abi Nahed, T.M. Abd El Aziz,
J. Escoffier, J. Bessonnat, C.-M. Fovet, M. De Waard, S. Hennebicq, V. Aucagne, P.
F. Ray, E. Schmitt, P. Bulet, C. Arnoult, Spermaurin, an La1-like peptide from the
venom of the scorpion Scorpio maurus palmatus, improves sperm motility and
fertilization in different mammalian species, Mol. Hum. Reprod. 23 (2016)
116–131, https://doi.org/10.1093/molehr/gaw075.
[133] C.N. Silva, K.P. Nunes, F.S. Torres, J.S. Cassoli, D.M. Santos, F.D.M. Almeida,
A. Matavel, J.S. Cruz, A. Santos-Miranda, A.D.C. Nunes, C.H. Castro, R.
A. Machado de Ávila, C. Chávez-Olórtegui, S.S. Láuar, L. Felicori, J.M. Resende, E.
R. da S. Camargos, M.H. Borges, M.N. Cordeiro, S. Peigneur, J. Tytgat, M.E. de
Lima, PnPP-19, a synthetic and nontoxic peptide designed from a phoneutria
nigriventer toxin, potentiates erectile function via NO/cGMP, J. Urol. 194 (2015)
1481–1490, https://doi.org/10.1016/j.juro.2015.06.081.
21
Biomedicine & Pharmacotherapy 170 (2024) 116015
[134] C.N. da Silva, K.N. Pedrosa, G.C. da Silva, P. da S. Cunha, T.F. Diniz, L.M.S. Maia,
F.D.M. Almeida, R.S. Gomez, V.S. Lemos, D.A. Gomes, M.E. de Lima, The
synthetic peptide PnPP-19 potentiates erectile function via nNOS and iNOS, Nitric
Oxide 113–114 (2021) 23–30, https://doi.org/10.1016/j.niox.2021.04.007.
[135] C.N. da Silva, K.P. Nunes, L.F.N. Dourado, T.O. Vieira, X.M. Mariano, A. da
S. Cunha Junior, M.E. de Lima, From the PnTx2-6 toxin to the PnPP-19
engineered peptide: therapeutic potential in erectile dysfunction, nociception,
and glaucoma, Front. Mol. Biosci. 9 (2022), https://doi.org/10.3389/
fmolb.2022.831823.
[136] L.F.N. Dourado, F.R. da Silva, C.R. Toledo, C.N. da Silva, C.P. Santana, B.L.
da Costa, M.E. de Lima, A. da S. Cunha Junior, Intravitreal injection of peptides
PnPa11 and PnPa13, derivatives of Phoneutria nigriventer spider venom,
prevents retinal damage, J. Venom. Anim. Toxins Incl. Trop. Dis. 26 (2020),
https://doi.org/10.1590/1678-9199-jvatitd-2020-0031.
[137] L.F.N. Dourado, C.N. da Silva, R.S. Gonçalves, T.T. Inoue, M.E. de Lima, A. da
S. Cunha-Júnior, Improvement of PnPP-19 peptide bioavailability for glaucoma
therapy: design and application of nanowafers based on PVA, J. Drug Deliv. Sci.
Technol. 74 (2022), 103501, https://doi.org/10.1016/j.jddst.2022.103501.
[138] C.N. da Silva, L.F.N. Dourado, M.E. de Lima, A. da Silva Cunha-Jr, PnPP-19
peptide as a novel drug candidate for topical glaucoma therapy through nitric
oxide release, Transl. Vis. Sci. Technol. 9 (2020) 33, https://doi.org/10.1167/
tvst.9.8.33.
[139] C. Silva, F. Silva, L. Dourado, P. Reis, R. Silva, B. Costa, P. Nunes, F. Amaral,
V. Santos, M. de Lima, A. Silva Cunha Júnior, A new topical eye drop containing
LyeTxI-b, A synthetic peptide designed from A lycosa erithrognata venom toxin,
was effective to treat resistant bacterial keratitis, Toxins 11 (2019) 203, https://
doi.org/10.3390/toxins11040203.
[140] F.R. da Silva, M.R.B. de Paiva, L.F.N. Dourado, R.O. Silva, C.N. da Silva, B.L.
da Costa, C.R. Toledo, M.E. de Lima, A. da Silva-Cunha, Intravitreal injection of
the synthetic peptide LyeTx I b, derived from a spider toxin, into the rabbit eye is
safe and prevents neovascularization in a chorio-allantoic membrane model,
J. Venom. Anim. Toxins Incl. Trop. Dis. 24 (2018), 31, https://doi.org/10.1186/
s40409-018-0168-5.
[141] Y. Kong, Y. Shao, H. Chen, X. Ming, J.-B. Wang, Z.-Y. Li, J.-F. Wei, A novel factor
Xa-inhibiting peptide from centipedes venom, Int. J. Pept. Res. Ther. 19 (2013)
303–311, https://doi.org/10.1007/s10989-013-9353-0.
[142] X. Ye, M. Chen, Y. Chen, X. Su, Y. Wang, W. Su, Y. Kong, Isolation and
characterization of a novel antithrombotic peptide from enzymatic hydrolysate of
agkistrodon acutus venom, Int. J. Pept. Res Ther. 21 (2015) 343–351, https://doi.
org/10.1007/s10989-015-9463-y.
[143] J. Ciolek, H. Reinfrank, L. Quinton, S. Viengchareun, E.A. Stura, L. Vera,
S. Sigismeau, B. Mouillac, H. Orcel, S. Peigneur, J. Tytgat, L. Droctové, F. Beau,
J. Nevoux, M. Lombès, G. Mourier, E. De Pauw, D. Servent, C. Mendre,
R. Witzgall, N. Gilles, Green mamba peptide targets type-2 vasopressin receptor
against polycystic kidney disease, Proc. Natl. Acad. Sci. USA 114 (2017)
7154–7159, https://doi.org/10.1073/pnas.1620454114.
[144] P. Perret, M. Ahmadi, L. Riou, S. Bacot, J. Pecher, C. Poillot, A. Broisat, C. Ghezzi,
M. De Waard, Biodistribution, stability, and blood distribution of the cell
penetrating peptide maurocalcine in mice, Int. J. Mol. Sci. 16 (2015)
27730–27740, https://doi.org/10.3390/ijms161126054.
[145] K. Münstedt, D. Funk, T. Riepen, E. Berkes, J. Hübner, Acceptance of
apitherapeutic methods in patients consulting general physicians or
gynaecologists, Complement Ther. Clin. Pract. 35 (2019) 154–157, https://doi.
org/10.1016/j.ctcp.2019.02.005.
[146] WHO Expert Committee on Biological Standardization, Guidelines for the
production, control and regulation of snake antivenom immunoglobulins, Annex
5, TRS No 1004, 2013. https://cdn.who.int/media/docs/default-source/
biologicals/blood-products/document-migration/antivenomglrevwho_trs_1004_
web_annex_5.pdf?sfvrsn=ef4b2aa5_3&download=true (accessed December 10,
2023).