⚠️ Auto-extracted by Claude on 2026-05-09 — class-page MOC drafted from the R36 round close. Member-compound pages are individually verified; this MOC summarises across them. Verify before relying on cross-class quantitative claims.
Peptide therapeutics — 503A bulks-list cluster
This page is a navigational MOC over the 12 peptide-class compounds covered in R36 (May 2026). It does not duplicate per-compound facts — each compound has an atomic page in molecules/compounds/ carrying primary-source citations. This page provides the regulatory frame, class-level pharmacology, evidence-quality summary, and wikilinks to navigate the cluster.
The cluster is defined by a regulatory event: the FDA Pharmacy Compounding Advisory Committee (PCAC) has been re-evaluating these substances for inclusion on the 503A bulk substances list across 2024–2026. PCAC voted against MK-677 in October 2024; the broader cluster remains under active review. Most clinic-grade telehealth peptide use was effectively halted by enforcement actions in this period.
The 12 compounds at a glance
| Compound | Class (mechanism) | Endogenous? | Aging-relevant claim | Strongest evidence | human-evidence-level |
|---|---|---|---|---|---|
| BPC-157 | tissue-repair-peptide | derived from gastric BPC | tendon/ligament/GI healing | preclinical + small human pilots (n<30 prospective) | limited |
| TB-500 | actin-regulatory-peptide (Tβ4 fragment) | fragment of endogenous TMSB4X | wound healing / angiogenesis | preclinical only; active metabolite Ac-LKKTE per Rahaman 2024 | preclinical-only |
| GHK-Cu | extracellular-matrix-remodeling | endogenous (plasma decline iconically cited but primary source = Pickart 1973 PhD thesis) | collagen/elastin synthesis; wound healing | strong topical clinical; injectable preclinical | limited (topical only) |
| Epitalon | telomerase-activation (claimed) | synthetic AEDG; distinct from epithalamin (bovine extract) | telomere lengthening; longevity (claim) | Khavinson cohorts used epithalamin extract, not synthetic epitalon | limited |
| MOTS-c | exercise-mimetic / mitohormesis-inducer | endogenous (mtDNA 12S rRNA-encoded) | mitochondrial-aging + metabolic | Lee 2015 Cell Metab + Reynolds 2021 Nat Commun (n=10 humans) | preclinical-only |
| DSIP | sleep-promoting-neuropeptide / HPA-axis-modulator | endogenous (rabbit thalamic isolation; human status partial) | sleep efficiency / latency | Schoenenberger 1977 PNAS + small 1980s-90s sleep RCTs | limited |
| Dihexa | growth-factor-receptor-agonism / HGF-mimetic (RETRACTED PRIMARY) | synthetic peptidomimetic | synaptogenesis / cognition | McCoy 2013 surviving primary; Benoist 2014 mechanism paper RETRACTED; BDNF and donepezil comparison claims absent from any surviving primary | none |
| MK-677 (ibutamoren) | growth-hormone-secretagogue / ghrelin-receptor-agonist | non-peptide small molecule | sarcopenia / sleep / lean-mass | multiple Phase 2/3 trials; Adunsky 2011 terminated early for CHF safety signal | strong (with safety caveats) |
| Melanotan II | melanocortin-receptor-agonist | synthetic α-MSH analog | tanning / appetite | Dorr 1996 Phase I (n=3); illicit-use case-series for AEs | limited |
| KPV | antimicrobial-peptide / anti-inflammatory (α-MSH 11-13) | endogenous α-MSH C-terminal fragment | gut inflammation / colitis | Dalmasso 2008 Gastroenterology; Laroui 2010 nanoparticle delivery | preclinical-only |
| Semax | neurotrophin-induction / neuroprotective-peptide | synthetic ACTH(4-7) analog | stroke recovery / cognition | Russian prescription drug; 22% infarct-volume reduction claim unverifiable in English literature | limited |
| LL-37 | antimicrobial-peptide / membrane-permeabilization | endogenous (CAMP gene → hCAP-18 → LL-37 by PR3 cleavage) | innate-immunity decline; wound healing | Sørensen 2001 mechanism + Miranda 2023 DFU RCT (n=25, granulation only — wound area NOT significant) | limited |
R36 round-close findings (verifier-derived)
The 13-page seed + verify pass surfaced an unusual concentration of fabricated or unverifiable marketing claims in this cluster. Each finding is documented on the relevant compound page; this MOC summarises for cross-class context.
Retracted or absent primary sources
- Dihexa: the c-Met / HGF mimetic mechanism paper (Benoist 2014, J Pharmacol Exp Ther 10.1124/jpet.114.218735) is retracted (November 2014; Expression of Concern September 2021; erratum April 2025). The two iconic marketing claims — “more potent than BDNF” and “outperformed donepezil” — were verified by the wiki-verifier (full PDF read of McCoy 2013) to be absent from any surviving primary source. McCoy 2013’s discussion section explicitly states the donepezil comparison is planned future work. The c-Met mechanism itself was attributed in McCoy 2013 to “(Benoist, Kawas, Harding, unpublished data)” — meaning the mechanism was never published in a surviving paper even before the 2014 retraction.
- Semax: the user-reported “22% infarct-volume reduction (2005 study)” claim was not locatable in PubMed or Crossref despite exhaustive search; the figure may originate from an inaccessible Russian-language gray-literature report. Tagged
#gap/unsourced #gap/no-fulltext-accesson the page. - Melanotan II: the user-reported “2021 melanoma incidence review” was not locatable after exhaustive search; the closest sources are case-report compilations (Habbema 2017, n=4 melanomas) and a qualitative user-experience study (Gilhooley 2021), neither of which is a melanoma-incidence review. Tagged
#gap/unsourced. - GHK-Cu: the iconic “200→80 ng/mL plasma decline (age 20→60)” claim traced to Pickart 1973 UCSF PhD thesis (unpublished), not a peer-reviewed primary measurement study. Reviews in 2015 + 2018 cite the 1973 thesis as the underlying source.
#gap/unsourcedretained — claim is widely cited but not in peer-reviewed literature.
Disambiguation surfaced (Mode A)
- Epitalon (synthetic AEDG tetrapeptide) ≠Epithalamin (bovine pineal extract). The widely-cited 266-person mortality-reduction cohort (Khavinson/Morozov 2003, PMID 14523363) and the 12-year cardiovascular cohort (Korkushko 2006) both used epithalamin (bovine extract), NOT synthetic epitalon. Verifier confirmed via PubMed abstracts. The conflation is a peptide-clinic marketing pattern; the wiki page documents the distinction explicitly.
- TB-500 (LKKTETQ fragment) ≠full Thymosin β4 (43-aa TMSB4X). Many “TB-500” wound-healing claims in marketing actually derive from full-Tβ4 studies (e.g., Philp 2004) and don’t apply to the fragment. Rahaman 2024 found Ac-LKKTE (a metabolite) is the active species, not parent TB-500.
- Melanotan II (cyclic, never approved) ≠Melanotan I / afamelanotide / Scenesse (linear, FDA-approved 2019 for erythropoietic protoporphyria). Conflation is common.
Seeder-fabricated or imprecise outcomes (R33 lesson confirmed)
- MK-677: Adunsky 2011 hip-fracture trial early termination due to congestive heart failure safety signal was missing from the seeder draft; verifier added. Authors concluded “unfavorable safety profile in this patient population.” Barzilai 2012 review’s “40-70% Ames/Snell dwarf” and “16% Igf1r-KO” lifespan percentages were attributed to the review but are not in its text — corrected to qualitative framing.
- MOTS-c: Zempo 2021 conclusion was REVERSED in the seeder draft — wiki said m.1382A>C variant “enriched in centenarian cohorts in Japan”; the paper actually concludes the variant “is unlikely to be involved with exceptional longevity” (7.7% vs 7.5% C-allele frequency, n=27,527). Corrected to
#gap/contradictory-evidenceframing. - Semax: Dmitrieva 2010 neurotrophin claim included NT-4 and p75NTR — paper measures only BDNF/NGF/NT-3 and TrkA/TrkB/TrkC. Both removed.
- DSIP: two distinct 1981 Schneider-Helmert papers (Experientia chronic-insomniacs vs IJCPTT healthy-volunteers) were conflated into one footnote; split into separate citations.
- TB-500: two fabricated author lists (Esposito 2012 added “Geldof L” who isn’t on the paper; Yu 1993 added “Bhatt SN, Chen LB” who aren’t on the paper). Both corrected via Crossref.
- MK-677: Svensson 1998 study design was misreported as crossover; it’s parallel-group. Age range was 18-40 vs actual 18-50.
Multiple DOI errors (canonical-source memory unreliable; R28 lesson confirmed)
Across the 12 compound pages, the verifier wave caught:
- Singh 2013 DOI (LL-37): wrong DOI resolved to a cyanophage RNA polymerase paper; corrected via PubMed PMID lookup.
- Pickart 1980 DOI (GHK-Cu): wrong DOI resolved to Keski-Oja sarcoma growth factors; corrected.
- Zempo 2021 DOI (MOTS-c): typo
aging.202593→aging.202529(different paper). - 4 PMID-only refs in MOTS-c (Woodhead, Yu, Zheng, Yoon) — three had wrong DOIs that returned 404 or wrong papers; corrected via PubMed/Europe PMC.
- Zhang 2019 page numbers (LL-37): wrong page range; corrected via Crossref.
Class-level pharmacology
Why peptides are hard to develop into drugs
- Enzymatic instability: most native peptides have plasma half-lives <30 min. Synthetic modifications (acetylation, cyclization, D-amino acids, polyethylene glycol conjugation) extend stability but alter pharmacology.
- Oral bioavailability: typically <2% for native peptides due to gastric proteases and intestinal-barrier limits. Most members of this cluster require parenteral (SC, IM, IV, intranasal) administration. Notable exceptions: MK-677 (small molecule, oral bioavailable).
- Manufacturing standards: telehealth-clinic-supplied peptides historically were not GMP-grade. Breindahl 2015 found 4.32–8.84 mg actual content vs 10 mg labelled in MT-II vials, with 4.1–5.9% impurities in 2/3 vials sampled. This is a class-wide concern.
- Immunogenicity: protein-derived peptides can elicit anti-drug antibody responses; relevant for chronic dosing.
Common claimed mechanisms in this cluster
| Mechanism class | Compounds | Evidence quality |
|---|---|---|
| Anti-inflammatory (NF-κB / MAPK) | KPV, BPC-157, GHK-Cu | KPV best-evidenced (Dalmasso 2008 IκBα kinetics); others mostly secondary |
| Wound healing / regenerative | BPC-157, TB-500, GHK-Cu, LL-37 | mixed; preclinical strong; human evidence thin |
| Neurotrophin / neuroprotective | Semax, Dihexa, BPC-157 | thin (Dihexa retracted; Semax Russian-only) |
| Mitochondrial / metabolic | MOTS-c | Lee 2015 + Reynolds 2021 |
| Antimicrobial | LL-37, KPV | LL-37 broad; KPV narrow |
| Sleep | DSIP, MK-677 | DSIP small RCTs; MK-677 stage IV (young) / REM (older) increases |
| Hormone-axis modulation | MK-677 (GH/IGF-1), Epitalon (melatonin/pineal claim), Melanotan II (melanocortin) | MK-677 strong; others speculative or contested |
| Tanning / cosmesis | Melanotan II (MC1R) | Phase I tanning n=3; illicit-use AEs |
Aging relevance — variable by compound
The strongest aging-relevance arguments in the cluster:
- MOTS-c — defensible. Mitochondrial-derived peptide, exercise-induced, Folate-AICAR-AMPK signalling, age-declining plasma levels. Hallmarks linked: mitochondrial-dysfunction + deregulated-nutrient-sensing.
- MK-677 — paradoxical. GH-IGF-1 axis stimulation is mechanistically opposite to canonical longevity (IGF-1 reduction extends lifespan in many models — Barzilai 2012). Short-term lean-mass + sleep benefits in older adults vs longevity-research preference for IGF-1 reduction is a substantive disagreement. Hallmarks linked: deregulated-nutrient-sensing + stem-cell-exhaustion.
- GHK-Cu — endogenous-decline-with-age narrative is widely cited but the primary-source plasma quantification is a 1973 unpublished PhD thesis. Topical clinical evidence solid; injectable preclinical only.
- Epitalon — telomerase-activation + longevity claims are the cluster’s marquee aging assertion, but the longevity-cohort evidence used the bovine extract (epithalamin), not the synthetic peptide.
- LL-37 — innate-immunity decline with aging is well-documented (Zhang 2019 dFB progenitor mechanism); therapeutic LL-37 hampered by host-cell toxicity at bactericidal doses.
The remaining seven compounds (BPC-157, TB-500, DSIP, Dihexa, Melanotan II, KPV, Semax) have no defensible aging-hallmark linkage with primary-source-grade evidence and carry hallmarks: [] in their frontmatter per the R36 wave-1 convention.
Regulatory status — FDA 503A bulks list
- 2024-10: PCAC voted against adding MK-677 (ibutamoren) to the 503A bulks list.
- 2025: enforcement actions effectively halted compounding-pharmacy distribution of most peptides in this cluster (BPC-157, TB-500, GHK-Cu, KPV, Semax, Epitalon, Dihexa, MT-II, MOTS-c, DSIP, LL-37).
- 2026: PCAC reconsidering parts of the cluster under different leadership (the user-supplied context); independent confirmation of meeting outcomes pending.
The wiki does not endorse or discourage any of these substances. The compound pages document evidence quality and safety profiles per CLAUDE.md citation discipline; the regulatory state is a fact about the FDA process, not an evidence claim about the substances.
See also
- intervention-classes — mechanism-class registry; new R36 classes added:
tissue-repair-peptide,actin-regulatory-peptide,extracellular-matrix-remodeling,exercise-mimetic / mitohormesis-inducer,sleep-promoting-neuropeptide / HPA-axis-modulation,growth-factor-receptor-agonism / HGF-mimetic,growth-hormone-secretagogue / ghrelin-receptor-agonist,melanocortin-receptor-agonist,antimicrobial-peptide / membrane-permeabilization,neurotrophin-induction / neuroprotective-peptide - camp — CAMP gene / hCAP-18 protein page (parent of LL-37 compound)
- finding-druggability — Open Targets workflow used to populate
druggability-tier:on individual compound pages - integrating-clinical-trials — ClinicalTrials.gov v2 API workflow used for
clinical-trials-active:counts
Knowledge gaps
- TMSB4X parent protein page — needed for full TB-500 biology context. Surfaced in R36 wave 1; queued for follow-up round.
- MOTS-c parent peptide page (
molecules/proteins/mots-c-peptide.mdper CLAUDE.md naming convention) — covers endogenous mtDNA-encoded biology distinct from therapeutic compound framing. - Receptor pages: GHSR (MK-677), MC1R/MC3R/MC4R/MC5R (Melanotan II), FPR2 (LL-37), c-Met/HGF (Dihexa — lower priority post-retraction). All implicit stubs from R36.
- PCAC primary-source confirmation — all bulks-list claims attributed to user-supplied context; FDA meeting transcripts not independently confirmed at time of round close.
needs-canonical-id — several compounds lack ChEMBL or DrugBank entries (peptides commonly unindexed); maintain on per-compound pages. no-fulltext-access — Russian-language Khavinson + Gusev primary literature largely closed-access; many class claims rest on abstract-level verification only.