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15.1 Introduction
The side effects associated with small molecule drugs have always created a need for an alternative
therapeutic preposition. In this context, the peptides represent a unique class of therapeutic agents
having features of small molecule drugs, large proteins, and other endogenous biologics [1]. All
the signaling molecules regulating the metabolic pathways are enzymes, hormones, and other
endogenous proteins. Consequently, the peptides emerge as an appropriate class of pharmaco-
therapeutic agents emulating natural entities when there is an imbalance or insufficiency in
endogenous secretion levels [2].
The discovery of peptides as therapeutic entities can be dated back to 1921–1922 when insulin
was first isolated from bovine and porcine pancreas, proving a boon for human civilization in the
management of type 1 diabetes [3]. In the 1950s, with the development of solution phase peptide
synthetic methods, several other peptides were chemically developed like synthetic oxytocin [4]
and synthetic vasopressin [5]. Later, in the mid-1960s, the peptide drug discovery was fueled by the
inception of solid-phase synthetic methods [6]. Implementation of more advanced techniques
such as microwave irradiation in both solid and solution phase peptide syntheses, chemical liga-
tions, and late-stage functionalizations further led to the clinical development of synthetic thera-
peutic peptides like recombinant insulin, gonadotropic-releasing hormones, leuprolide, and
goserelin [7]. Since 2000, about 40 peptides have attained FDA approval as drugs. Peptide drugs
have a vast therapeutic repertoire [8–12]. Currently, more than 200 peptides are under active clini-
cal trials, along with several others undergoing preclinical investigations [13].
The peptide molecules can potentially and selectively bind to larger protein interfaces, thereby
advocating low off-target side effects and toxicity [14]. With the advances in computational
approaches, the rational design and development of therapeutic peptides have become more effec-
tive [15]. In silico molecular docking methods enable accurate prediction of protein structure, sur-
face topology, and interaction affinities. Peptide docking has been divided into template-based and
template-free docking depending on the requirement size of input data [16]. The physics-based
15
Rational Design of Peptides and Protein Molecules in
Drug Discovery
Ipsa Padhy
1
, Abanish Biswas
2
, Chandan Nayak
3
, and Tripti Sharma
1,4
1
Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University),
Bhubaneswar, Odisha, India
2
Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Ranchi, Jharkhand, India
3
School of Pharmaceutical Education and Research, Berhampur University, Berhampur, Odisha, India
4
School of Pharmaceutical Sciences and Research, Chhatrapati Shivaji Maharaj University, Navi Mumbai, Maharashtra, India
328
molecular simulations are currently well integrated with emerging artificial (AI)- and alfafold
(AF)-based tools for reshaping the peptide discovery landscape [17].
In this chapter, we discuss various methods utilized in the design and development of therapeutic
peptides with a special focus on current technological advancements. We emphasize the therapeutic
applications of peptides. A comparative analysis between the peptide and small molecule drugs
respective to their pharmacodynamic and a pharmacokinetic property has also been conversed.
We outline various state-of-the-art peptide docking methods. An overview of available specific
peptide docking software tools is provided.
15.2 Peptides as Therapeutics
The management of diseases by small molecule drugs is impeccable. However, the side effects
associated with therapeutic small molecules have also generated a need for alternative therapeutic
entities. In this scenario, peptides present themselves as a distinct class of therapeutic candidates.
Metabolic disorders and cancers have been the thrust disease areas driving peptide drug discover-
ies [18]. The emergence of antimicrobial-resistant pathogens has also irked the development of
novel peptide antibiotics [19]. Gastrointestinal (GI) disorders have also provided a research area
eliciting a lot of interest in the development of peptides as potential therapeutic treatment
options [20].
15.2.1 Peptide Antibiotics
Antimicrobial resistance has become a global health issue basically arising due to overprescribing
antibiotics for nonbacterial infections or frequent misuse of antibiotics as prophylactics [21]. With
growing microbial resistance, the last-line antimicrobials have entered the pre-antibiotic era as well
a very slow pace in discovery of newer broad-spectrum antimicrobials for multidrug-resistant path-
ogens, the therapeutic utilization of peptide antibiotics becomes the foremost important [22, 23].
Moreover, peptide antibiotics stand high as a source of new antimicrobials [24].
The peptide antibiotics or host defense peptides are front-line defense entities in both prokary-
otes and eukaryotes. The antimicrobial peptides have broad-spectrum inhibitory activity against
bacteria, protozoan parasites, pathogenic fungi, and viruses. The peptide antibiotics are diverse
with respect to their structure, physicochemical properties, and mechanism of action. The peptide
antibiotics are isolated from bacteriophages, bacteria, fungi, mollusks, amphibians, arthropods,
mammals, and plants as well [25]. The first reported peptide antibiotic was gramicidin, which
showed inhibitory activity against many Gram-positive bacteria. It was isolated from the soil bac-
terium Bacillus brevis [26]. The antimicrobial peptide database (APD3) has cataloged more than
3000 peptide antibiotics [27].
In general, the peptide antibiotics comprise 50 amino acid residues. The majority of the AMPs
are cationic, with more than 45% hydrophobic residues [27]. The cationic nature, as well as the
hydrophobic residues of these peptides, generate an amphipathic backbone facilitating the bacte-
rial membrane infiltration [28]. Different models have been demonstrated for targeting microbial
cell membranes by the antimicrobial peptides (AMPs) (Figure 15.1).
Cathelicidin LL-37 peptides induce anionic lipid clustering to permeate bacterial membranes
and rupture the phospholipid bilayer by carpet/toroidal models. The proline-rich peptides target
bacterial ribosomes, while lantibiotics and cyclotides can both bind to phosphatidylethanola-
mines (PEs) [29–32]. Rather, these peptides may work synergistically for optimal outcomes.
329
Finally, AMPs can boost the immune response to further clear invading pathogens. All of these
mechanisms make it difficult for pathogens to develop resistance.
15.2.1.1 Peptides in Bone Diseases
Bone diseases are a wide group of musculoskeletal disorders that often require high drug doses
for effective therapy. However, such high doses of small-molecule drugs evoke adverse effects.
In such cases, bone tissue-targeted pharmacotherapy is a prerequisite peptide that has been
developed in the last three decades for the treatment of bone disorders, especially degenerative
bone resorption triggered by osteoporosis and bone metastasis [33–35]. Numerous peptide ther-
apeutic candidates can be classified into four categories like bone resorption inhibitors (W9,
OP3-4, RANKL inhibitor peptide), bone formation stimulators (B2A, P1, P2, P3, P24, P15,
TP508, OGP, PTH), dual bone resorption inhibitors, and bone formation stimulators and bone
targeting peptides [36]. The designed peptides inhibited bone resorption by antagonizing
actions of TNF-α and RANKL, modulating RANK–RANKL signaling pathways, mimic Loop3
of RANKL, and blocked the RANKL-binding activity and RANKL-induced differentiation of
osteoclast, blocking NEMO/IKK-β interactions and suppressing of the activity of the IKK com-
plex inhibiting TNF-α-induced NF–κB signaling pathway for bone resorption preventing
inflammatory bone resorption.
15.2.1.2 Peptides in Cancer
Immunotherapy majorly attacks the tumor cells by targeting immune checkpoints. FDA has
approved monoclonal antibodies (MABs) for cancer therapy by targeting specific immune check-
points. Although very effective, MABs have some disadvantages associated with high immuno-
genicity, poor solubility, and very high cost [37]. Being smaller in size, good stability, and less
immunogenicity, the peptides have been seeking serious attention in the arena of cancer therapy
and diagnosis. The peptides are applied for cancer theranostics in many different ways (Figure 15.2).
Antimicrobial peptide
Bacterial cell
membrane
Toroidal pore model
Carpet model
Conformational change in
peptide and attachment to
bacterial cell membrane
Barrel stave model
Bacterial cell rupture Peptide translocation to intracellular
targets
Figure 15.1 Models displaying the mechanism of membrane disruption by peptide antibiotics.
330
The peptides can be labeled with dyes, radioisotopes, or other specific molecules for cancer
diagnosis or imaging. The peptides are conjugated with nanocarriers for targeted therapy. The
peptides have been developed as vaccines. Peptides are directly used as targeted pharmacothera-
peutics [38, 39].
The peptide-based imaging probes bind to receptors expressed on the cell surface (α-integrins,
somatostatin receptor, transferrin receptor, neurotensin receptor), within the intracellular matrix
(cyclin A, cyclin kinase) or extracellular matrix (fibronectin, matrix metalloproteinases, prostate-
specific antigen) [38]. The tumor distribution can be visualized by single photon emitted computed
tomography imaging/scanning techniques. Octreoscan and depreotide are radiolabeled conjugates
of somatostatin peptide approved by the FDA for diagnosis of neuroendocrine and lung can-
cers [40]. Although depreotide was later withdrawn. Tc-3PRGD2 is an iodine labeled α-integrin-
based peptide probe developed for the detection of thyroid cancer [41]. On a similar note, cancer
radiotherapy with isotope-labeled peptides was developed. A good example is Lutetium 177 dota-
tate, somatostatin labeled with radioactive lutetium 177. It is FDA-approved for the treatment of
gastroenteric neuroendocrine cancers [42–44]. The major side effect of targeted radiotherapy is
inevitable damage to normal tissues surrounding the metastatic tissues [45].
Peptides are also conjugated with anticancer drugs, genes, and RNAs for targeting tumor
cells [45]. Adriamycin-conjugated AN-150 and AN-207 (luteinizing releasing hormone analogs)
were found to be effective against endometrial and ovarian cancers in phases I and II clinical trials.
The PEGylated NGR peptide conjugated to liposome polycation DNA effectively delivered the
small interfering RNA to tumor cells in vivo and, decreased expressions of c-Myc and induced
apoptosis [46]. The cell-penetrating peptides act as carriers for other peptides, nucleic acids, and
drugs to target tumor sites [47]. Antigenic peptides like TERT572Y have been developed as anti-
cancer vaccines (lung cancer), which trigger immune activities of killer T cells or helper T cells by
Tumor cells
Linker
Nanocarrier
Anti-cancer
drug
Radiolabeled
nucleotide
Peptide
A
B
C
D
E
F
Imaging agent
Antibody
Immunity booster
Targeted delivery
Immunotherapy
Targeted therapy
Targeted radiotherapy
Tumor diagnosis
Figure 15.2 Peptide-based cancer theranostics. (A) Peptide vaccine; (B) nanocarrier-loaded peptides;
(C) peptide conjugated to the antibody; (D) peptide conjugated to anticancer drug; (E) peptide conjugated
to radionucleotide; and (F) peptide conjugated to the imaging agent.
331
coupling to MHC I and II complexes [48]. Peptides conjugation to specific antigens induce vaccine
immunogenicity [49, 50]. Itself peptides exert anticancer effects. PD-1/PD-L1 is one of the major
signaling pathways being targeted for anticancer peptide drug discovery. Notably, PD-LI peptide
mimics like PL120131, DS-I & II, FITC-YT-16, and NY-12 were developed that demonstrated prom-
ising antitumor potency against preclinical cancer models [51–54].
Interestingly, natural spider venom toxins like Hanatoxin-1 from the Chilean spider [55] and
Lafr26, a porogenic peptide isolated from the venom of Lachesana species spiders [56] have shown
effective anticancer potency against colon and lung cancers in vitro. The natural venom-derived
peptides exert anticancer activity by blocking potassium ion channels and specific transmembrane
receptors Many other naturally derived and semisynthetic peptides have shown promising anti-
cancer activities, like aurein 1.2, BMAP-27, BMAP-28, brevinine, cecropin A and B, citropin 1.1,
gaegurins, HMGB 1, HNP 1, 2 and 3, hBD3, and PR-39 against leukemia, bladder cancer, breast
cancer, and colon cancers in vitro. The potency of natural antimicrobial peptides such as LL-37,
magainin 2, LfcinB, melittin, and tachyplesin 1 against cancers has also been revealed [57]. A
chemically synthesized θ-defensin peptide analog exerted anti-breast cancer activity, probably by
membrane rupturing activity [58].
15.2.1.3 Peptides in Metabolic Diseases
T2DM has been successfully treated with peptide drugs, including GLP-1 receptor agonists [59].
Exenatide, liraglutide, lixisenatide, dulaglutide, and semaglutide are some FDA-approved peptide
drugs for clinical use in type 2 diabetes [60]. Clinical trial reports have proven that GLP-1 receptor
agonists like lixisenatide are instrumental in improving diabetic nephropathy [61]. Moreover, it
was reported that liraglutide and semaglutide antiatherosclerotic potency [62, 63].
The renin–angiotensin–aldosterone system (RAAS) is an exclusive target for the pharmacother-
apy of cardiac disorders by peptides. Synthetic angiotensin II was approved by the FDA in 2017 for
increasing blood pressure via intravenous infusion in adults with septicemia or other distributed
shock [64]. Four peptides (WPRGYFL, GPDRPKFLGPF, WYGPDRPKFL, and SDWDRF) isolated
from Tetradesmus obliquus microalgae inhibited the angiotensin-converting enzymes (ACEs) [65].
IRW, an egg white-derived tripeptide exhibited antihypertensive activity in vivo by upregulating
angiotensin-converting enzyme (ACE2) [66]. The natriuretic peptide receptors pose as excellent
targets for cardiovascular drugs [67, 68]. Nesiritide is a recombinant human BNP that was approved
by the FDA in 2001 for the treatment of acutely decompensated heart failure in patients [69, 70].
NPs act mainly through NPR-A and/or NPR-B receptors, while NPR-C is mainly used for scav-
enging NPs [71]. Cenderitide (from green mamba snake) is a dual NPR-A/NPR-B agonist in an
active clinical trial and is having a safe therapeutic index [16, 72]. Infusing vasoactive intestinal
peptides increased the concentration of myocardial vasoactive intestinal peptides and reversed
existing myocardial fibrosis in rats [73, 74]. Cyclopeptide RD808 attenuated β1-adrenergic induced
myocardial injury in vivo [75]. The central adrenocorticotropin-releasing factor (CRF)-related
peptide system is currently attracting increasing attention as a target for the prevention of cardio-
vascular disease [76, 77].
15.2.1.4 Peptides in Gastrointestinal Diseases
The gut microbiome of human secretes a plethora of antimicrobial peptides. GI diseases and excessive
use of antibiotics degrade the symbiotic gut microflora that usually acts as a gut defense system. GI
diseases are being now targeted by peptides. Proline-arginine-39, isolated from porcine bone mar-
row and lymphoid tissue, exhibited antibacterial, immunomodulatory, and intestinal epithelial
repair functions and may provide a safe alternative therapy for IBD [78]. Subcutaneous injection
332
of teduglutide a GLP-2 analogue developed by recombinant DNA technique, increased intestinal
absorption in patients with short bowel syndrome (SBS) [79, 80]. EGF, erythropoietin, and hepato-
cyte growth factor have also shown therapeutic potential in SBS [81].
Periplanetasin-2 isolated from the American cockroach blocked the mucosal damage and inflam-
mation induced by Clostridium difficile toxin A [82]. Preincubating or co-incubating (Clostridium
perfringens endotoxin) CPE with the claudin-4 extracellular loop ECL-2 peptide significantly inhib-
ited CPE-induced luminal fluid accumulation and histological lesions in rabbit intestinal loop [83],
indicating synthetic peptide ECL-2 can be used to negate food poisoning. Cathelicidin produced from
the human colon defended Salmonella typhimurium infection by obstructing bacteria infiltration
into the colon epithelium by upregulating Toll-like receptor-4 and releasing pro-cytokines [84].
15.2.2 Advantages and Limitations of Peptide Therapeutics
The peptide drugs basically mimic endogenous hormones, growth factors, neurotransmitters, ion
channel ligands, or anti-infective agents. Typically, they attach to cellular receptors and induce
specific effects intracellularly. The peptide drugs, in comparison to other therapeutic biologicals,
incur less production cost as well as display less immunogenetic [2]. Therapeutic peptides, in com-
parison to small molecule drugs, are target-specific and have minimal side effects owing to shorter
half-life. The tissue accumulation by therapeutic peptides is low [85]. Therapeutic peptides have
two intrinsic drawbacks, membrane impermeability and poor in vivo stability, which represent
major stumbling blocks for peptide drug development [86, 87].
15.2.3 FDA-Approved Peptide Therapeutics
Peptide drug discovery is targeted at various diseases, such as autoimmune, endocrinological, skin,
bone disorders, reproductive and cardiovascular diseases, and diseases related to metabolic dys-
function. However, the prime focus has remained on anticancer and antimicrobial therapeutics,
justified by the high number of drug approvals for these indications (Table 15.1).
15.2.4 Peptide-Based Entities in Clinical Trials
Peptides currently in clinical trials (Table 15.2) are being investigated for a wide range of applications,
including microbial infections, diabetes, hormonal disorders, and cancer [7]. Interestingly, some
trials are being carried out simultaneously in two phases, such as phase I/II or II/III, to hasten the
approval process (https://www.clinicaltrials.gov). The data highlight that FDA approvals of peptide
drugs had been predominantly via parenteral rather than oral routes of administration. However,
advances in chemical modifications have led to an almost equivalent presence of oral peptides in
clinical trials to that of the intravenous route. This is a promising trend, given that oral administra-
tion is expected to widen the applicability of peptide drugs.
15.2.5 Peptide Synthesis and Diversification
With rapid technological innovations in the fields of synthetic biology, biotechnology, and chemical
sciences, peptide drug discovery and development has achieved enormous success. In this chapter,
we recapitulate the existing state of art techniques (Figure 15.3) employed for peptide synthesis
and diversification.