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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5435_Библиотеки_им_академика_М_И_Перельмана
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Type-I peptidomimetics, also known as pseudopeptides, are created using a structure-
based drug design approach. These peptidomimetics have functional groups that create
significant interactions with the binding sites of the receptors, but they nonetheless
closely resemble the peptide backbone. Some units, such as p-turns, which imitate brief
peptide secondary structure fragments, have been employed to make lead compounds.
The peptide bond in a transition state or product state for the enzyme-catalyzed reac-
tion served as the model for several early protease inhibitors. Because they substitute
amide bonds with metabolically stable units on parent peptide amino acid units, pyrro-
linones, for instance, have side chains with peptide-like properties that fit the active
sites of the majority of peptidases and are resistant to normal proteolysis.
14.11 The use of venom peptidomimetics
in medicine
Animal venoms are sophisticated bioactive concoctions that are primarily made up of
proteins and peptides. Probably the most well-known animal venoms are from snakes,
spiders, scorpions, and cone snails. Although larger proteins, such as enzymes, are also
present, the short (3–9 kDa) disulfide-rich peptides that contain the inhibitor cysteine
knot (ICK) pattern make up the majority of the first three venoms. ICK peptides are
very structurally stable and largely act on membrane channels or neuronal receptors
in the nervous system [40, 41]. The diversity in molecular structures of venom-derived
toxins and their targets is depicted in Figure 14.5. Snake venoms are typically composed
of 20 to >100 components, the majority (>90%) of which are peptides and proteins, with
the principal bioactivities varying depending on the snake species, including neurotox-
icity, hemotoxicity, and cytotoxicity. The makeup of venom varies greatly between spe-
cies and even within the same species.
Defensins are tiny proteins found throughout life that serve as host defense pepti-
des and have antibacterial and/or immunological signaling properties. The defensins
contained in viperid venom act on the Na
+
and K
+
channels of plasma membranes in-
cluding the sarcolemma of muscle cells, and accumulate in lysosomes, generating anal-
gesic, neurotoxic, myotoxic, and cytotoxic effects. The buildup in lysosomes is an
uncommon cytotoxic mechanism among snake poisons. Furthermore, the architectures
of defensins are distinct from those of other channel-binding toxins. Although they can
be plentiful in specific venoms, defensins are typically rare, accounting for less than 1%
of total venom [42].
Venom peptides have a wide range of folds. Up to 14 different types of folds were
observed in the case of animal poisons acting on ion channels. Along with other desir-
able properties such as short size and high stability, fold diversity can be employed to
benefit the functional derivation of venom peptides. Indeed, the active sites of venom
peptides can be replaced with functional ly unrelated pharmacophores of biological
364 Kannan Sadasivam, Venkata Surya Kumar Choutipalli, and Lalitha Gummidi
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significance in order to profit from the advantageous peptide properties. The CD4-
binding surface of the HIV-1 gp120 envelope glycoprotein, for example, has been suc-
cessfully transplanted into the structure of a scorpion toxin with the scaffold. This
strategy results in the development of novel anti-HIV drugs with in vitro efficacy.
Venom peptides with uniq ue pharmacophores are promising candidates for biologi-
cal, biotechnological, and medicinal applications. If the novel compounds have the
requisite medicinal characteristics, a therapeutic development could be envisaged.
Other methods of functional derivation are possible that do not require the re-
placement of the peptide pharmacophore with an external one. In that instance,
α-bungarotoxin : α1 nAChR
Snake
captopril : ACE
α-conotoxin ImI : AChBP
μ-conotoxin KIIA : Na
v
1.2/β2
exendin-4 : GLP-1R
DE
LIzard
Scorpion
charybdotoxin : K
v
1.2–2.1 AaH2 : Na
v
PaS-Na
v
1.7
DkTx and RTX : TRPV1 ProTx-II : Na
v
1.7-Na
v
AB
PcTx1 : ASIC1 Dc1a and TTX : Na
v
PaS
CB
A
Cone snail Spider
triflin : SSP2
MitTx : ASIC1
botrocetin : vWF : GPIb Cobra Venom Factor : factor B
Figure 14.5: Molecular structures of various venom-derived toxins and targets along with their PDB
accession codes (reproduced with permission from [41]).
14 Computer-aided design of peptidomimetic therapeutics 365
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many peptide features such as cell targeting, receptor recognition, membrane translo-
cation, and nucleic acid binding are derived. It is worth mentioning that in some cir-
cumstances, removing the peptide’s initial pharmacological action is required to
avoid undesired side effects. For example, maurocalcine’s pharmacological activity on
intracellular ryanodine-sensitive calcium channels can be reduced in order to employ
just its cell-penetration property for the cell entry of bigger nonmembrane permeable
substances such as entire proteins.
14.12 Infectious disease-treating peptidomimetics
While the careful use of effective antimicrobials is an important step in reducing diffi-
culties and costs associated with MRSA infections, new solutions to address this global
concern must be investigated. The separation of natural and synthesized antimicrobial
peptides (AMPs) has shown tremendous promise in recent years as a potential option
for innovative therapeutic agents to treat illnesses caused by multidrug-resistant organ-
isms. AMPs have been isolated from bacteria (termed bacteriocins), marine animals,
plants, birds, insects, frogs, and the human innate immune response since their discov-
ery. AMPs are typically made up of a short chain of 12–100 amino acids connected to-
gether by peptide bonds. They are typically cationic (have at least two positive charges),
which allows them to interact with negatively charged components of the bacterial
membrane and cell wall; additionally, AMPs are amphipathic, which is thought to allow
them to target and partition into bacterial cell membranes. Antibacterial peptides have
been shown to attack intracellular targets in bacteria such as inhibiting macromolecu-
lar synthesis, inhibiting nucleic acid or protein synthesis, binding directly to nucleic
acids, or interfering with cell wall synthesis [43, 44].
Naturally occurring peptides, such as human defensins, have been found to play a
significant role in the immunological response to invading pathogens. Because they are
frequently constitutively expressed or generated in response to microbial virulence fac-
tors such as lipopolysaccharide (in Gram-negative bacteria), these molecules serve a key
role in innate immunity. However, research has revealed that in the presence of specific
cytokines, leukocytes (including human natural killer cells, B cells, and T cells) can be
encouraged to create peptides such as defensins, implying that they may play an impor-
tant role as effector molecules in adaptive immunity. Thus, peptides with limited or no
antimicrobial activity but immunostimulatory properties (to selectively upregulate the
innate immune response to an infection without overstimulation of pro-inflammatory
mediators) have the potential to be used as therapeutic agents against Staphylococcus
aureus (particularly for intracellular infection clearance). This activity can be paired
with a subtherapeutic dose of a standard antibiotic to provide a two-pronged attack on
the bacterial infection: direct action against the pathogen (through the antibiotic) com-
bined with immune response stimulation (by the peptide) to eliminate the illness.
366 Kannan Sadasivam, Venkata Surya Kumar Choutipalli, and Lalitha Gummidi
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Multidrug-resistant infections, particularly those caused by S. aureus, pose a sig-
nificant public health concern that must be addressed. The decreasing efficacy of
present antibiotics in the face of increasing bacterial resistance highlights the critical
need for the development of alternate therapeutic options and techniques to conven-
tional antibiotics. Because of their complicated mechanism of action, AMPs represent
a significant potential ally in the fight against bacterial illnesses. Bacterial resistance
to AMPs is unlikely to evolve quickly. Though these peptides have several limitations
that must be addressed before they can be used in systemic applications (including
stability in physiological condi tions and a limited ability to penetrate intracellular
compartments where S. aureus tends to escape the host immune response), success in
animal studies and human clinical trials supports the use of AMPs as decolonizing
agents and topical agents (either alone or in combination with conventional antibiot-
ics) for the tetracycline resistance. Furthermore, because AMPs can modulate the host
immune response, their potential use as immunomodulatory agents to stimulate the
host immune response to clear an infection caused by multidrug-resistant bacteria is
an exciting avenue for researchers to pursue in the future.
14.13 Medicinal peptidomimetics against parasites
PMX is an aspartyl protease that processes proteins required for Plasmodium para-
sites to penetrate and exit host erythrocytes during the symptomatic asexual stage of
malaria. The consensus motif, SFhE (h = hydrophobic amino acid), denotes a con-
served cleavage area in PMX substrates. Peptidomimetics based on the P3P1 locations
of the consensus motif were developed and demonstrated effective and selective PMX
inhibition. Modeling of the peptidomimetics in association with PMX revealed that
PMX favors Phe in the P1 position, di-substitution at the carbon of the P2 moiety, and
a hydrophobic P3 group.
By inhibiting PMX substrate processing, the peptidomimetics were found to halt
asexual Plasmodium falciparum parasites during the schizont stage. PMX is effectively
inhibited by the peptidomimetics 26, 34, 37, and 38 that most closely mirrored the PMX
substrate sequence. When compared to PMIX, PMV, and human aspartyl proteases,
these peptidomimetics are extremely selective for PMX. Weak inhibition of PMIX was
anticipated given the great homology and similarity of the consensus sequence between
these aspartyl proteases, but 49c (2) also exhibits the same selectivity profile, indicating
that the P1ʹ methyl benzylamine motif contributes to selectivity. The antimalarial tool
compound WM382 has been shown to have potent dual inhibition of PMX and PMIX
[45]. Peptidomimetics 26, 34, 37, and 38 kill P. falciparum parasites effectively, and this
activity is strongly related to PMX biochemical inhibition. To demonstrate that 38’spar-
asite activity was caused by PMX inhibition, 38 was found to inhibit SERA5 processing
indirectly via inhibiting SUB1 maturation. At 10 M, 38 inhibited ASP processing, albeit
14 Computer-aided design of peptidomimetic therapeutics 367
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this was insufficient, showing that 38 was killing the parasite through inhibiting PMX.
Furthermore, compound 38 was shown to inhibit parasite development at the schizont
stage of asexual parasites, which is consistent with the phenotype of previously re-
ported PMX inhibitors 1 and 2 [46] and the role of PMX in processing ligands required
for merozoite egress from the schizont and the host erythrocyte. When compared to the
recognized drug-like inhibitors WM382 (1) and 49c (2), the peptidomimetic tool com-
pounds presented here have drawbacks. The peptide like character of peptidomimetic
drugs limits membrane permeability and in vivo absorption, and metabolism of peptide
like compounds is frequently difficult to rectify, limiting their utility in in vivo models
and development as an antimalarial treatment. Overall, mimicking of the PMX P3P1
substrate sequence has offered a channel to block PMX and kill P. falciparum parasites.
It has contributed to a better understanding of PMX substrate specificity and provided
a template for future design of PMX-targeted antimalarials.
14.14 Cancer-fighting therapeutic peptidomimetics
Cancer cells have upregulated and overexpressed cell surface receptors in the plasma
membrane. Normal cells lack or have very low levels of these receptors, allowing
them to be utilized for cancer diagnosis [47]. By using molecular imaging, peptidomi-
metics may be able to act on diagnostic locations. Because of its promise to improve
cancer diagnosis, staging, and therapy regimens, molecular imaging has made signifi-
cant development. Diagnostic imaging approaches bas ed on molecular imaging are
among the most useful noninvasive technologies for visualizing, describing, and mea-
suring biological processes at the cellular and molecular levels. The most frequent im-
aging techniques used to identify cancer at various stages are magnetic resonance
imaging, positron emission tomography, com puted tomography, and single-photon
emission computed tomography. Proteins, DNAs, mRNAs, and microRNAs, as well as
imaging techniques, can be used as new diagnostic tools. Although imaging techni-
ques are very efficient, they do have drawbacks, such as their high cost [48].
Imaging probes coupled to specific ligands that recognize overexpressed recep-
tors in angiogenic tumors, such as integrin, are one promising technique to finding
molecular markers. Several synthesized peptides and peptidomimetics that are pow-
erful integrin ligands and antagonists that block integrin-mediated tumor-stimulating
biological pathways are related to the diagnostic applications of peptidomimetics. Nu-
merous integrins have been linked to poor prognosis, including v3, v5, 51, 64, 41, v6,
and v8; most relevant research focus on v3. There is considerable interest in peptido-
mimetics that replicate the guanidine and carboxylate pharmacophores found in RGD
(Arg-Gly-Asp) peptides for this integrin [49].
368 Kannan Sadasivam, Venkata Surya Kumar Choutipalli, and Lalitha Gummidi
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14.15 Computational tools and strategies
for peptidomimetics design
In the current research on peptidomimetics, computer-assisted tools are extensively
used. The computational tools are extensively used to design novel chemical entities
and gain a deeper understanding of molecular recognition processes involving peptides
and peptidomimetics, leveraging existing knowledge about the selected biological tar-
gets. Moreover, the conformational analysis, homology modeling of proteins, docking
studies, and de novo design in various areas of interest, pharmacophore modeling,
ADMET prediction, and optimization of lead compounds are the integral parts of the
computational approaches. These tools are particularly focused on investigating pep-
tide-peptide receptor interactions and PPIs with therapeutic significance. By utilizing
these computational techniques, we aim to advance our understanding by summarizing
the recent developments in theoretical approaches in peptidomimetic-based therapies
leading to a new branch of drug development known as computational peptidol-
ogy [50].
Computational tools are used to predict and analyze the structural and physico-
chemical properties of peptides and proteins. The computer-aided design of peptidomi-
metics is depicted in Figure 14.6 and Figure 14.7. By understanding the key interactions
and binding patterns, they can design peptidomimetics with improved bioactivity and
specificity. Large databases of chemical compounds can be efficiently screened using
computational tools to identify potential peptidomimetics candidates that might exhibit
the desired biological activity. This saves time and resources in the initial stages of drug
discovery. Integrating bioinformatics techniques with molecular simulations proves to
be a valuable approach for identifying promising drug-candidate peptides. The en-
hanced precision in calculating binding free energy enables a more comprehensive un-
derstanding of the molecular binding interactions, ultimately leading to a higher
success rate in the design process [51–54].
In this context, numerous computational tools have been created to design variants
of peptidomimetics [55]. Notable among them are empirical methods, machine learning,
and stochastic approaches, all aimed at optimizing peptides through random processes
[56]. Machine learning models efficiently screen and optimize a limited number of se-
quences that can be further assessed experimentally. Among these machine learning
strategies, particular attention has been given to the quantitative structure–activity re-
lationship (QSAR) model [57]. QSAR techniques are widely employed to establish corre-
lations between mol ecular structure and biological properties through numerical
analysis. QSAR techniques have found extensive use in pharmaceutical drug research
and are now being applied to the design and discovery of AMPs [58, 59]. It employs
physicochemical descriptors to predict the biological activity of peptides based on their
amino acid sequences [60]. In other study, Cruz-Monteagudo et al. [61] introduced a
multicriteria QSAR model to assess the antibacterial and hemolytic activities of cyclic b-
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Figure 14.6: Computer-aided design of peptidomimetics (reproduced with permission from [55]).
370 Kannan Sadasivam, Venkata Surya Kumar Choutipalli, and Lalitha Gummidi
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(a) (b)
Figure 14.7: (a) Schematic representation of various methodologies for peptide design through bioinformatics tools such as ligand-based, target-based, and
de novo. (b) Computational strategies to transform peptides in peptidomimetics (reproduced with permission from [69]).
14 Computer-aided design of peptidomimetic therapeutics 371
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hairpin cationic peptidomimetics (Cb-H). This approach demonstrated an 80% accuracy
in both training and external validation sets. Additionally, they conducted virtual
screenings to identify selective antibacterial cyclic b-hairpin cationic peptidomimetics
(Cb-HCPs). Similarly, a recent study by Wang et al. [62, 63] demonstrates a promising
direction for developing practical predictors by creating a user-friendly and publicly ac-
cessible web server to forecast novel AMPs. However, it is important to note that most
cheminformatics efforts have primarily focused on antibacterial activity, largely over-
looking the equally significant hemolytic aspect. Although exceptions exist, recent QSAR
studies have emerged, considering both the bioactivity and toxicity of drug candidates
for various therapeutic applications [64, 65]. Di Leva et al. [66] conducted a study where
they employed computational techniques like MetaD and classical MD simulations to
facilitate the transformation of peptides into more active peptoids/peptidomimetics.
Their research focused on targeting avb6 RGD-integrin in one case and the eukaryotic
translation initiation factor 4E (eIF4E) in another [67–69].
Overall, computational tools provide an invaluable platform for peptidomimetic
drug discovery, enabling faster and more efficient identification and optimization of po-
tential therapeutic candidates. They complement experimental approaches and contrib-
ute significantly to advancing the field of peptidomimetics in pharmaceutical research.
14.16 Drug development and future perspectives
on peptide therapeutics
Diabetes mellitus and type 2 diabetes mellitus (T2DM) are characterized by an ac-
quired insulin insufficiency and are common in middle-aged and older adults. T2DM
has been successfully treated using peptide medications like as GLP-1 receptor ago-
nists (GLP-1RAs) and insulin, the most well-known peptide therapy. GLP-1 is an endog-
enous growth hormone released by ileum L-cells. Its receptors are found in the
pancreas, the peripheral and central neurological systems, the he art and blood ves-
sels, the kidneys, the lungs, and the gastrointestinal mucosa. In a glucose-dependent
way, GLP-1 interacts with its receptor to stimulate islet-cells to secrete insulin, block
islet-cell glucagon release, promote satiety, and delay stomach emptying. Endogenous
GLP-1 is rapidly degraded by dipeptidyl peptidase-4 and inactivated. Synthetic GLP-
1RAs are essential to inhibit GLP-1 receptor degradation in order to prolong the stimu-
lation time. Since the FDA approved the first GLP-1RA, exenatide, in 2005, several
GLP-1RAs have entered the clinic including liraglutide (2009), lixisenatide (2013), dula-
glutide (2014), and semaglutide (2017). These GLP-1RAs significantly lower glycosylated
hemoglobin and average blood glucose levels after injection and improve fasting
blood glucose [70].
Viruses are parasites that infect all living things including humans, animals,
plants, microbes, and archaea. Viral infections, such as Ebola hemorrhagic fever, in-
372 Kannan Sadasivam, Venkata Surya Kumar Choutipalli, and Lalitha Gummidi
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fluenza, and acquired immune deficiency syndrome (AIDS), have historically plagued
humans. Despite substantial efforts in antiviral medication development over the last
two decades, which resulted in the licensing and clinical usage of many antiviral
treatments, some of these diseases, such as AIDS, remain untreatable. Because of pep-
tides’ great specificity and efficacy, research into antiviral peptides has become a
prominent topic. Antiviral peptides primarily inhibit infection by targeting the virus
or its host. Enfuvirtide, the first antiviral peptide approved, is a 36-amino acid peptide
that prevents HIV infection by binding to the heptad-repeat domain of gp41 (HIV en-
velope protein). Boceprevir and telaprevir, antiviral peptide medicines, were licensed
for clinical treatment of hepatitis C virus (HCV) in 2011. They both bind to the HCV
NS3/4A serine protease and suppress its activity, preventing HCV replication in the
host. Preclinical and clinical studies are being conducted on antiviral peptide medica-
tion candidates such as myrcludex B against HBV and HDV, flufirvitide against influ-
enza virus, and sifuvirtide against HIV-1 [71, 72].
Peptides, in addition to being derived from drugs, can also be derived from food.
The peptide Asn-Pro-Trp-Asp-Gln (NPWDQ), derived from hydrolyzing casein (a major
milk protein), greatly reduced the entrance of the food allergen ovalbumin into
human intestinal Caco-2 cells, implying that this peptide may improve the function of
the intestinal epithelial barrier. Casofensin is a peptide present in fermented milk,
and early injection of -casofensin reduced indomethacin-induced intestinal damage
and inflammation by protecting goblet cells and facilitating wound healing in vivo.
Indomethacin-induced intestinal damage shares clinical, histological, and pathophysi-
ological features with Crohn’s disease [73], implying that casofensin could be used as
an adjuvant therapy for Crohn’s disease.
14.17 Conclusions
Because of their particular biochemical properties and therapeutic potential, peptides
have emerged as a distinct class of therapeutic agents in recent years. Although pepti-
des outperform small compounds and large biologics in some ways, they frequently
suffer from membrane impermeability and poor in vivo stability due to amino acid
inherent constraints. Extensive research has been conducted in the areas of peptide
drug development, manufacturing, and optimization in order to overcome these dis-
advantages. The combination of traditional lead peptide discovery methods with
novel technologies such as rational design and phage display provides a dependable
way for rapidly developing effective and selective lead peptides. The employment of
chemical and biological recombination synthetic techniques alone or in combination
allows for the efficient and reliable manufacture of synthetic peptides on vast scales.
To improve their stability and physiological activity, these peptides can be further
changed in a site-specific way via chemical synthesis or genetic code extension.
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