Therapeutic peptides: current applications and future directions

Overview

Wang and colleagues (Zhejiang Sci-Tech University, Nanjing University of Chinese Medicine, Hangzhou First People’s Hospital affiliated with PLA Joint Logistic Support Force, the Chinese Academy of Medical Sciences in Lanzhou, and Lanzhou University) review the state of therapeutic peptide drug development in 2022, covering discovery strategies (natural-hormone mimicry, peptide drug candidates from natural products, non-ribosomal peptides, rational design based on protein-protein interactions, phage display), chemical and recombinant production (solid-phase peptide synthesis via Fmoc-SPPS and Boc-SPPS, recombinant DNA technology, semi-synthesis, genetic code expansion with non-canonical amino acids, site-specific PEGylation), chemical modification (alanine-scan, backbone modification, side chain modification, cyclization, α-helix and β-sheet stabilization), and current and future therapeutic applications across diabetes mellitus, cardiovascular disease, gastrointestinal and gastric disease, oncology, and antiviral therapy (including SARS-CoV-2 peptide vaccine candidates). The review is a secondary narrative synthesis with no primary measurements; its relevance to the Heavy Metal Index is indirect — it provides the methodological and pharmaceutical-industry context for any future wiki work on heavy-metal exposure routes specific to therapeutic and black-market peptide products.

Why this matters

• It catalogues the approved therapeutic-peptide drug landscape: 33 non-insulin peptide drugs approved worldwide since 2000 (Table 1, p.2), with first-approval years and indications, plus a complement of peptides in clinical trials (Table 2, p.3). For any future wiki page surveying the legitimate-pharmaceutical baseline against which black-market peptide products are compared, this is the most current peer-reviewed roster.
• It documents the chemical-synthesis routes used in current pharmaceutical peptide production (Fmoc-SPPS, Boc-SPPS, recombinant DNA technology, semi-synthesis, genetic code expansion, enzymatic synthesis), which are the upstream pathways that determine which residual reagents — including metal-containing reagents — could in principle remain in a peptide product as a synthesis-residue contamination class. Methods detail relevant to any later metals-in-peptides routing is concentrated in the “Synthesis and modification of therapeutic peptides” section (pp.6-9) and Fig. 6, Fig. 7, and Fig. 9.

Key concepts and structure

The review is organised into five top-level sections: introduction (p.1), therapeutic peptides — advantages and drawbacks (pp.2-4), developmental path of therapeutic peptides — discovery, production and optimization (pp.4-10), current development and application of therapeutic peptides in diseases (pp.11-17), and conclusion and perspective (p.18). The reference list contains 535 entries spanning 1921-2021.

Approved peptide drugs since 2000

Table 1 (p.2) lists 33 non-insulin peptide drugs approved worldwide since 2000 by target and indication. Therapeutic areas covered include the GLP-1 receptor (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide), GLP-2 receptor (teduglutide), guanylate cyclase C (linaclotide, plecanatide), calcitonin receptor (pramlintide), GnRH receptor (abarelix, degarelix), the 20S proteasome (carfilzomib), NOD2 protein (mifamurtide), VIP1 receptor (aviptadil), oxytocin receptor (atosiban, carbetocin), TRH receptor (taltirelin), melanocortin receptors (bremelanotide, afamelanotide, setmelanotide), PTH1 receptor (teriparatide, abaloparatide), NPR-A receptor (nesiritide), AT1 receptor (angiotensin II), β2-receptor (icatibant), gp41 (enfuvirtide), GHRH receptor (tesamorelin), N-type calcium channels (ziconotide), thrombopoietin receptor (romiplostim), human erythropoietin receptor (peginesatide), pulmonary surfactant (lucinactant), CaSR (etelcalcetide), somatostatin receptors (pasireotide, the radiolabelled somatostatin-receptor agonists Lutetium Lu-177 dotatate and Edotreotide gallium Ga-68). Top-selling non-insulin peptide drugs worldwide in 2019 (Fig. 1, p.3) were dulaglutide (~USD 4.4 billion), liraglutide, semaglutide, octreotide, glatiramer, teriparatide, lanreotide, leuprolide, linaclotide, and goserelin.

Peptide drug synthesis routes

Two major solid-phase peptide synthesis (SPPS) strategies are described (p.6, Fig. 6): Fmoc-SPPS (uses piperidine deprotection; preferred for most current syntheses; aspartimide formation in certain sequences is a documented impurity-formation pathway addressed by mixed-solvent strategies, microwave-assisted heating, pseudo-prolines, low-substitution resins, N-α-alkyl Asp-Gly dipeptides, HOBt, and Oxyma Pure additives) and Boc-SPPS (uses trifluoroacetic acid deprotection and hydrogen fluoride cleavage; advantageous for long peptide synthesis but limited by toxicity of HF). Automated peptide synthesisers (e.g., CEM Liberty PRIME, CSBio II) are described as enabling parallel sequential synthesis of up to 192 different sequences with infrared or microwave heating; GMP manufacture continues to prefer mild reaction conditions to minimise side reactions and impurities. Recombinant DNA technology (p.8) is described as the preferred method for industrial preparation of large peptides and proteins with disulfide bonds; semi-synthesis combines synthetic peptides with recombinant DNA-expressed peptides to incorporate non-canonical amino acids and modifications.

Genetic code expansion and PEGylation chemistry

Genetic code expansion (p.8-9, Fig. 8) enables site-specific incorporation of non-canonical amino acids (ncAAs) into recombinantly produced proteins. The review describes the four-component system: an ncAA with desired chemical and physical properties; a unique codon (amber stop UAG or quadruplet) assigned to it; an orthogonal tRNA that suppresses that codon and does not crosstalk with endogenous tRNA; an orthogonal aminoacyl-tRNA synthetase that charges the ncAA onto the orthogonal tRNA without crosstalk. More than 200 ncAAs have been encoded across Escherichia coli, yeast, mammalian cells, viruses, and animals. Figure 10 (p.10) lists 15 representative ncAAs by structure (pAzF, NEAK, pAcF, HepoK, pNO2F, 3NO2Tyr, SO3Tyr, pIpa, pBpa, pBO2pa, PenK, ACPK, DiZPK, ONBK, BCN, BocK, FSY).

PEGylation chemistry (p.9, Fig. 9) is described as a prevalent strategy for modifying therapeutic peptides and proteins since the 1970s; more than ten PEGylated protein therapeutics are currently on the market. Three site-specific conjugation routes are illustrated:

1. Cu(I)-catalysed alkyne-azide cycloaddition (CuAAC) between an alkyne-derivatised PEG and an azide-bearing ncAA (e.g., p-azido-phenylalanine, pAzF). This was the first ncAA-mediated mono-PEGylation method, demonstrated on superoxide dismutase (SOD) in 2004 by Deiters and colleagues (Wang 2022 reference 249). The same approach was applied to interferon-α2b by Zhang and colleagues (reference 250).
2. Copper-free strain-promoted cycloaddition between a strained cyclooctyne-PEG and an azide-bearing ncAA, allowing PEG conjugation without the copper catalyst. Three resulting IFN-α2b variants showed significantly higher biological activities and better pharmacokinetic profiles than other variants and the wild-type molecule in rodent models.
3. Hydrazone formation between an aldehyde- or ketone-bearing ncAA and an alkoxyamine-PEG (e.g., site-specific PEGylation of human growth hormone via p-acetyl-phenylalanine).

The review also notes the use of Cu(I)-catalysed click chemistry to conjugate PEG to ncAA-modified live-attenuated viral particles in the context of HIV-1 vaccine development (p.11). The review does not report any residual-copper measurements; Cu(I) catalyst use is described as a synthetic methodology, not as a contamination concern.

Peptide-modification chemistry beyond PEGylation

Side chain modification with homoarginine, benzyloxy-tyrosine, β-phenylalanine; backbone modification by D-amino acid substitution, methyl-amino acid insertion, β-amino acid incorporation, peptoid construction; cyclization (head-to-tail, side chain-to-side chain, backbone-to-side chain, side chain-to-tail) with lactam bridges (via Glu/Asp + Lys side chains), disulfide bonds (Cys/homo-Cys), and bis-electrophilic linkers; α-helix stabilisation by stapled peptide methods (hydrocarbon, lactam, biselectrophilic, nucleophilic cross-links) and hydrogen-bond surrogate (HBS) approaches; β-sheet and β-strand stabilisation with D-Pro-L-Pro templates. Fig. 7 (p.7) illustrates these strategies schematically.

Therapeutic applications surveyed

The review covers six therapeutic-area applications: type 2 diabetes mellitus (GLP-1 receptor agonists, GLP-1RAs, and insulin; Fig. 11 mechanism diagram, p.12); cardiovascular disease (natriuretic peptides ANP, BNP, CNP; nesiritide; cenderitide; food-derived peptides targeting renin-angiotensin system; Fig. 12, p.13); gastrointestinal disease (teduglutide for short bowel syndrome, linaclotide for chronic constipation, β-casofensin from milk fermentation, food-derived intestinal-barrier peptides; Fig. 13 GLP-2 structure, p.13); gastric disease (CGRP, ghrelin, motilin, novokinin from ovokinin, GEBP11 tumour-targeting peptide for gastric cancer); oncology (peptide-based imaging probes, peptide-conjugated nanomaterials, peptide vaccines, peptides as targeted drugs; Fig. 14, p.16); and antiviral therapy (enfuvirtide for HIV-1, boceprevir and telaprevir for HCV, the COVID-19 peptide vaccine candidates in development at the time of writing).

Methods (brief)

This is a narrative review. The authors do not declare a systematic search strategy, inclusion/exclusion criteria, PRISMA flow, or risk-of-bias assessment. The reference list contains 535 entries spanning Banting et al. 1922 on pancreatic extracts in diabetes (reference 205) through 2021 publications; the bulk of references are post-2000 with a concentration on 2015-2021. The authors are based at Zhejiang Sci-Tech University (Hangzhou), Nanjing University of Chinese Medicine, Hangzhou First People’s Hospital affiliated with PLA Joint Logistic Support Force, the Institute of Materia Medica at the Chinese Academy of Medical Sciences and Peking Union Medical College (Beijing), and Lanzhou University. Funding is acknowledged from the Zhejiang Provincial Natural Science Foundation of China (LD22H310004), the National Natural Science Foundation of China (No. 81770176), the “Pioneer” and “Leading Goose” R&D Program of Zhejiang (No. 2022C03005), the special support plan for Zhejiang Province high-level talents (No. 2019R52011), the Zhejiang Provincial Natural Science Foundation of China (LQ20H300005), and Program of Xinmiao Talents in Zhejiang Province (2021R406062). C.F. and R.W. are listed as conception and co-design of the work; L.W., N.W., and W.Z. as preparation and writing of manuscript; X.C., Z.Y., G.S., and X.W. as data collection, interpretation and preparation of figures and tables. C.F. is on the editorial board of Signal Transduction and Targeted Therapy but was not involved in the manuscript-handling process; the remaining authors declare no competing interests.

The journal (Signal Transduction and Targeted Therapy, Springer Nature) is open-access; the article carries the “OPEN” badge and ”© The Author(s) 2022” attribution consistent with the CC BY 4.0 default for Nature open-access publications. Received 17 August 2021, revised 13 January 2022, accepted 17 January 2022, published online 14 February 2022.

Implications

• Microbiome: Not relevant. The review does not engage the gut microbiome or the heavy-metal-microbiome axis. WikiBiome federation is unlikely to draw on this source.

Limitations

Related evidence

• Remediation evidence — drivers and interventions
• Studying Peptide-Metal Ion Complex Structures by Solution-State NMR
• Peptides Used for Heavy Metal Remediation: A Promising Approach

Update history

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