Wang 2022 — Therapeutic peptides: current applications and future directions

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.
• It describes Cu(I)-catalysed alkyne-azide cycloaddition (CuAAC, click chemistry) as the site-specific conjugation method behind several mono-PEGylated protein therapeutics (e.g., Cu(I)-catalysed mono-PEGylation of superoxide dismutase via genetic incorporation of p-azido-phenylalanine, p.9; the Cu(I)-catalysed alkyne-azide click reaction used to attach PEG to ncAA-modified live-attenuated virus particles, p.11). Copper is not on the HMTc 10-analyte list and so does not enter frontmatter, but the documented use of copper catalysis in the synthesis pathway of approved peptide therapeutics is an HMI-relevant methodological data point that would otherwise have to be reconstructed from the primary references.
• It identifies radiolabelled-peptide therapeutics (Lutetium 177 dotatate, Edotreotide Gallium-68, the Tc-99m and Iodine-131 radiolabelled tumour-targeting peptides described in Fig. 14 and the surrounding text) as an approved class of peptide drug. These are radioactive isotopes used as therapeutic or diagnostic payloads attached to peptide carriers, not stable heavy-metal contaminants in the HMTc sense; readers building a metals-in-peptides corpus should not conflate the two.

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

• Certification: The review contributes no occurrence data, no exposure data, and no analytical-method data, so it does not move any HMTc threshold-setting work. Its value for HMTc is indirect — it documents the chemistry routes used in current pharmaceutical peptide production, which is upstream methodological context for any future HMTc workstream addressing trace-metal residues in peptide therapeutics or in unregulated peptide products distributed outside the pharmaceutical regulatory system.
• App: No routing to ingredient or product pages. This source contributes no consumer-facing data and bears on no food, beverage, personal-care, or environmental matrix.
• Courses: Useful as a single-source orientation to the current pharmaceutical-industry landscape for therapeutic peptides — approved drugs, clinical-trial pipeline, synthesis routes, modification chemistry, and emerging application areas. Should be paired with a peptide-pharmaceutical regulatory reference (USP <232>/<233> for elemental impurities, ICH Q3D, or the equivalent EMA/PMDA guidance) for any course module that treats residual-metal limits in peptide therapeutics; this review does not engage that regulatory layer.
• 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

This is a narrative review with no declared inclusion/exclusion criteria, no PRISMA flow, and no risk-of-bias assessment. The author conflict-of-interest disclosure notes that C.F. is on the editorial board of Signal Transduction and Targeted Therapy but was excluded from manuscript handling; no other competing interests are declared. The review is wide in scope — discovery, production, modification, and six therapeutic-area applications — and correspondingly shallow on each topic; readers needing the methodological detail behind any individual claim must consult the primary references. The review does not engage trace-metal residual chemistry, elemental-impurity testing (USP <232>/<233>, ICH Q3D), or any contamination-occurrence dataset for therapeutic peptides; readers building a metals-in-peptides corpus should treat this source as a roster-of-approved-drugs and synthesis-route reference, not as evidence on contamination occurrence, exposure, or analytical method. None of the HMTc 10-analyte priority metals (Pb, tAs, Cd, MeHg, tHg, iAs, Ni, Al, Cr-VI, Sn) are addressed by the review; the only metal substantively discussed is copper, in the context of Cu(I) catalysis of click-chemistry conjugation, and copper is not an HMTc analyte. The radiolabelled peptide therapeutics described (Lutetium 177, Gallium-68, Tc-99m, Iodine-131) are radioactive isotopes used as therapeutic or diagnostic payloads, not stable heavy-metal contaminants, and are out of scope for HMI’s contamination-and-exposure mission.

Wiki pages this source may touch

• remediation-evidence

Verification notes

Existing-page check. DOI grep (10.1038/s41392-022-00904-4), raw_handle grep (MFK_23-therapeutic-peptides-current-applications-and-f), and cite-key glob (wang2022-therapeutic-peptides-*) over wiki/sources/ on 2026-06-08 returned no matches. The only pre-existing wang2022- page (wang2022-heavy-metals-gastric-cancer-plasma-china.md) is a different paper on metal occurrence in gastric-cancer plasma in China; the cite-key disambiguator -therapeutic-peptides-review distinguishes this entry. This is a NEW source page — no prior version to merge-enhance.

Evidence tier. B (secondary narrative review). The paper reports no primary measurements and declares no systematic search strategy. A-tier is reserved for primary peer-reviewed studies and authoritative agency monographs; this is neither.

Metals frontmatter. Empty. From the HMTc 10-analyte priority list (Pb, tAs, Cd, MeHg, tHg, iAs, Ni, Al, Cr-VI, Sn), the review addresses none substantively. The only metal that recurs in the review’s body is copper (Cu(I) catalysis in CuAAC click chemistry for PEGylation, p.9; copper-catalysed click reaction in HIV-1 vaccine ncAA modification, p.11) and Cu is not on the HMTc 10-analyte list. Radiolabelled-peptide therapeutics (Lutetium 177, Gallium-68, Tc-99m, Iodine-131) appear in the oncology section as radioactive payloads attached to peptide carriers, not as stable heavy-metal contaminants in HMTc’s contamination-and-exposure sense, and so do not justify a metals: entry. The mitigation/remediation-evidence wikilink is included in the “Wiki pages this source may touch” section because Karen’s manual-fetch curation places this paper in the heavy_metals_peptides folder of the Black Market Peptide Metal Survey, alongside shalev2022-peptide-metal-nmr-review and luo2024-peptides-heavy-metal-remediation; this source provides the legitimate-pharmaceutical-peptide baseline against which black-market peptide metal-contamination work will be framed.

Ingredients, products, matrices, jurisdictions frontmatter. All empty. The source measures nothing in any food, beverage, personal-care, or environmental matrix; it reviews the pharmaceutical-industry development of therapeutic peptides as drug products. No jurisdiction is studied — author affiliations are in mainland China, but the review is conceptually international (covers FDA approvals, worldwide drug-market data, global clinical-trial pipeline). No regulatory framework is the subject of analysis, so jurisdictions is empty.

Sample size. Null. This is a review with no sampling frame.

Brand firewall (Part 12). The review names a roster of marketed therapeutic-peptide drug products by their International Nonproprietary Name (INN) — the review’s intro reports “nearly 40 peptide drugs being approved worldwide” (p.1) and the Conclusion reports “More than 80 therapeutic peptides have reached the global market to date” (p.18) — exenatide, liraglutide, semaglutide, dulaglutide, teduglutide, linaclotide, ziconotide, enfuvirtide, leuprolide, degarelix, etc. — and uses several proprietary brand names from the pharmaceutical industry to identify market-share data (Trulicity for dulaglutide, Victoza for liraglutide, Rybelsus for semaglutide; Fig. 1 caption, p.3). Per the strict-reading-locked-2026-05-17 brand-firewall rule, these names are not contamination-value attributions and do not constitute brand ranking by contamination level; the review reports drug-market sales rankings, which is a different category of attribution. However, since the wiki defaults to no brand attribution, the wiki page summarises the drug-market data without reproducing the brand-name-to-sales-rank table. Approved-drug INNs (exenatide, liraglutide, etc.) are used in this page in the same way regulatory and pharmacopoeial references use them — as the generic name for a class of pharmaceutical actives, not as a contamination-value attribution. Scientific-method vendor names (CEM Liberty PRIME, CSBio II peptide synthesisers; Fig. 6 caption text) are retained under Exception 2 (locked 2026-05-17). No firewall action required.

HMTc firewall (Part 2). The review contains no HMTc-threshold language, no claims of “consistent with the literature consensus” framing in either direction, no consumer-audience risk advisories on peptide therapeutics, and no occurrence or exposure language for metals in peptides. The Conclusion and Perspective section (p.18) is a forward-looking summary of peptide-drug research directions and does not propose any threshold or safety claim. No firewall action required.

Date arithmetic. Received 17 August 2021, revised 13 January 2022, accepted 17 January 2022, published online 14 February 2022 — all consistent with the year frontmatter (2022). Article DOI 10.1038/s41392-022-00904-4 resolves to Signal Transduction and Targeted Therapy 2022, 7:48.

Audit subagent (2026-06-08) verdict: REVISE. Five checks (numerical fidelity, slug vocabulary, speciation/methods, brand firewall, HMTc firewall) returned three ✅, one ⚠️, and one ❌.

• Check 1 numerical-fidelity ❌ flagged that the Methods (brief) section said “Banting et al. 1923 on pancreatic extracts in diabetes (reference 205)” but reference 205 in the source is dated 1922: “Banting, F. G. et al. Pancreatic extracts in the treatment of diabetes mellitus. Can. Med Assoc. J. 12, 141-146 (1922).” Verified against PDF p.18 ref 205 — finding correct; corrected the publication year from 1923 to 1922. The separate “Frederick Banting in 1921” date elsewhere in the source body refers to Banting’s isolation work, not the 1922 publication, and is not affected by this correction.
• Check 1 numerical-fidelity ⚠️ flagged that the Verification notes’ “approximately 60 marketed therapeutic-peptide drug products” figure does not appear in the source; the source’s own figures are “nearly 40 peptide drugs being approved worldwide” (p.1 intro) and “More than 80 therapeutic peptides have reached the global market to date” (p.18 Conclusion). Verified against PDF p.1 and p.18 — finding correct; replaced the “~60” disambiguation with both of the source’s own figures (40 approved and 80 reached the market), which is the language a hostile reviewer can verify directly against the paper.
• Checks 2, 3, 4, 5 returned ✅ — no further corrections applied.

Reviewer’s note on scope fit. This paper is in the “Black Market Peptide Metal Survey / heavy_metals_peptides” Manual Fetch Kimi folder alongside shalev2022-peptide-metal-nmr-review, luo2024-peptides-heavy-metal-remediation, and several other peptide-and-metals sources. Like Shalev 2022, this paper is in scope per the 2026-06-02 commit 3f47f95 — scope: mitigation/remediation is in-scope, not a skip, but its actual wiki contribution is the narrowest yet: it is a generalist therapeutic-peptide development review with no direct heavy-metals content. Its HMI-relevant payload is (a) the roster of approved peptide therapeutics that anchors the legitimate-pharmaceutical baseline for any black-market-peptide comparator work and (b) the documentation of copper-catalysed click chemistry as a synthesis route used in approved PEGylated peptide drugs (copper is not an HMTc analyte but the methodology is documented here for future reference if a metals-in-peptides workstream needs to trace synthesis-residue pathways). Readers expecting heavy-metals occurrence or contamination data in this paper should be redirected to the sibling sources in this same folder.

Page history

The five most recent substantive edits to this page. The full version history lives in git; when DOI minting comes online (see schema docs), each entry below will also link to a version-pinned DataCite DOI.