pe
pep-10681 v1 CC-BY-SA-4.0

Skin-pigmentation research peptide (MSH-B)

A hormone fragment first found in sea lamprey, tested in the lab for effects on skin pigment cells and appetite signals; used only as a research tool, not a medicine.

statusbioassayed targetMC4R length20 aa refs9
snapshot in_vitro 0% confidence
Class
Melanotropin peptide (melanocyte-stimulating hormone variant)
Status
Research peptide; no approved therapeutic status identified
Best-supported effect
Greater potency than alpha-MSH and MSH-A in a frog skin melanotropin bioassay (in vitro / ex vivo assay evidence only)
Main caveat
Evidence is limited to a single 1995 bioassay; no animal or human data are attached to this card
status 4 / 5 · 2 verified on platform
prediction metrics boltz-2 1.0
ipTM0.944
pTM0.892
avg pLDDT80.7
ranking score0.835
STRUCTURE · PEP-10681 × MC4R
ranking0.835
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
boltz-2 1.0 · mmCIF ↓ download
sequence20 aa
15101520
VQESADGYRMQHFRWGQPLP
in the news 2 articles
overview readme

Snapshot

Class: Melanotropin peptide (melanocyte-stimulating hormone variant)
Evidence tier: In vitro / assay evidence
Status: Research peptide; no approved therapeutic status identified
Best-supported effect: Greater potency than alpha-MSH and MSH-A in a frog skin melanotropin bioassay (in vitro / ex vivo assay evidence only)
Main caveat: Evidence is limited to a single 1995 bioassay; no animal or human data are identified


What this is

MSH-B peptide is a 20-amino-acid (eicosapeptide) melanotropin isolated from the sea lamprey (Petromyzon marinus). It contains the canonical melanotropin-core sequence shared with alpha-MSH and related melanocyte-stimulating hormones. In the single published assay identifieds source, MSH-B demonstrated approximately 10-fold greater potency than alpha-MSH and approximately 100-fold greater potency than MSH-A in a frog skin bioassay, an established model for melanotropin receptor activity.


Evidence map

Evidence layerGradeWhat it supports
HumanNone identifiedNo human trial or clinical data are identified
AnimalNone identifiedNo dedicated animal study data are identified
In vitro / bioassayWeakSingle frog skin assay demonstrating melanotropin receptor activity and relative potency versus alpha-MSH and MSH-A
ComputationalNone identifiedNo structure prediction or docking data are identified
MechanismPlausibleMelanotropin-core sequence implies melanocortin receptor engagement; receptor subtype specificity not established in attached source

The evidence base is restricted to one 1995 comparative bioassay. No independent replication data are identified.


Claim check

ClaimVerdictEvidence layerConfidence
Melanotropin receptor activity in bioassaySupported (in vitro / ex vivo frog skin assay)In vitroLow — single assay, 1995; no independent replication in attached source
Greater potency than alpha-MSH in frog skin assay (~10-fold)Supported (in vitro / ex vivo)In vitroLow — single published assay; assay system is not a mammalian model
Greater potency than MSH-A in frog skin assay (~100-fold)Supported (in vitro / ex vivo)In vitroLow — single published assay; no replication in attached source
Melanotropin activity in mammalian or human systemsNot establishedNoneLow — no mammalian cell, animal, or human data are identified

Assay conditions

This section reports conditions used in the assay described in the attached source. It does not establish animal or human exposure.

ContextSystemAssay conditionTimepointEndpointLimitation
Frog skin melanotropin bioassayFrog skin preparation (classical melanotropin bioassay)Peptide concentration not individually extracted in sourceNot individually extractedMelanotropin potency (skin darkening response); relative to alpha-MSH and MSH-AEx vivo bioassay system; does not establish mammalian receptor binding, selectivity, or in vivo activity; single 1995 publication; no mammalian or human translation established

Mechanism

MSH-B contains the melanotropin-core amino acid sequence present in melanocyte-stimulating hormones, which engage melanocortin receptors (MC1R through MC5R in mammals). The frog skin bioassay measures skin-darkening responses mediated through melanophore pigment dispersion, a classical functional readout for melanotropin receptor engagement. The specific melanocortin receptor subtype(s) engaged by MSH-B, and whether its enhanced potency relative to alpha-MSH reflects altered receptor binding affinity, selectivity, or downstream signaling, are not established in the attached source. Target confidence is inferred from peptide class and assay context; no direct binding data are identified.


Chemistry

FieldValue
Sequence (one-letter)VQESADGYRMQHFRWGQPLP
Full notationH-Val-Gln-Glu-Ser-Ala-Asp-Gly-Tyr-Arg-Met-Gln-His-Phe-Arg-Trp-Gly-Gln-Pro-Leu-Pro-NH2
Length20 amino acids (eicosapeptide)
TopologyLinear
C-terminal modificationAmidation (C-terminal -NH2)
OriginIsolated from sea lamprey (Petromyzon marinus)
Molecular weightNot reported in attached source
CASNot reported in attached source
Sequence confidenceNeeds review — sequence is sourced from a single vendor/catalog entry; no cross-source verification is identified

Open questions

  • Mammalian receptor binding: Which melanocortin receptor subtype(s) does MSH-B engage, and does its higher potency relative to alpha-MSH reflect subtype selectivity or general affinity enhancement? The frog skin assay does not resolve this.
  • In vivo activity: No animal model data are identified. Whether the frog skin potency advantage translates to mammalian or human physiological systems is unknown.
  • Mechanism of potency enhancement: The structural basis for MSH-B's approximately 10-fold and 100-fold potency advantage over alpha-MSH and MSH-A respectively is not explained in the attached source.
  • Independent replication: The single 1995 Takahashi et al. bioassay result has not been independently replicated in attached source material.
  • Sequence verification: The sequence is derived from a single catalog source; confirmation against the original Takahashi et al. primary publication is warranted.
Hypotheses5 directions▾ collapse

Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.

openupdated 2026-06-05

Could the lab test that first measured this peptide have pointed scientists at the wrong target in the body?

If the peptide turns out to bind the skin receptor (MC1R) more tightly than the appetite receptor it was labeled with, it could become a starting point for new treatments for pigmentation conditions or sun-damage-linked inflammation, for people who need alternatives to existing therapies. The finding would also be a caution: a single frog-skin assay shaped years of assumptions about where this molecule acts.

The hypothesis
The extended N-terminal segment (VQESADGYRM) of MSH-B confers selective high-affinity binding to MC1R over MC4R, meaning the annotated primary target (MC4R) reflects the frog skin assay readout rather than the peptide's actual highest-affinity mammalian receptor.
Why it’s plausible
Alpha-MSH (SYSMEHFRWGKPV) has comparable low-nanomolar affinity at both MC1R and MC4R, with the HFRW core driving pharmacophore engagement. MSH-B retains the HFRW motif but replaces the N-terminal SYSME region with a 10-residue lamprey-specific extension (VQESADGYRM) that includes a tyrosine (Y8) and a charged RM dipeptide flanking the core. Frog skin melanophores express predominantly MC1R-equivalent receptors, so the frog bioassay potency advantage could reflect MC1R selectivity rather than MC4R potency. The Boltz-2 complex prediction with high iptm (0.944) was run against MC4R, but binding energy alone does not exclude higher affinity at MC1R. Published binding tables (10.1016/j.molmet.2021.101206) show that even small N-terminal extensions in melanocortin analogs shift MC1R versus MC4R selectivity substantially.
Why it matters
If MSH-B is actually an MC1R-selective agonist despite its annotation as MC4R-primary, its therapeutic niche shifts from obesity and energy homeostasis to pigmentation disorders, photoprotection, and anti-inflammatory dermatology, and it would be a structurally novel MC1R scaffold from a non-mammalian lineage.
Plausibility.64
Novelty.57
Impact.79
Basis · grounding1 paper · 3 computed/notes
[1]
sequenceHFRW core at positions 12-15 confirmed; N-terminal VQESADGYRM is distinct from mammalian alpha-MSH SYSMEH prefix
[2]
noteSingle frog skin assay used for all potency claims; frog melanophore receptor subtype not characterised in source
[3]
paper
Tabulated binding affinities show N-terminal sequence context strongly modulates MC1R vs MC4R selectivity across melanocortin analogs
doi: 10.1016/j.molmet.2021.101206
[4]
structureBoltz-2 iptm 0.944 against MC4R indicates the peptide can dock MC4R, but does not establish it is the preferred subtype
openupdated 2026-06-05

What if a molecule could make your gut release the 'I'm full' hormones more strongly than anything we have now?

If this holds, the peptide could stimulate cells in the colon to release natural satiety hormones (GLP-1 and PYY) at higher levels than the body normally produces after a meal, potentially helping people with obesity feel full sooner. Because the action would happen in the gut rather than the brain, it might avoid some of the mood or mental-health side effects linked to centrally acting appetite drugs.

The hypothesis
MSH-B activates MC4R in enteroendocrine L cells to stimulate peptide YY and GLP-1 secretion, and its higher intrinsic potency versus alpha-MSH produces a proportionally greater postprandial satiety hormone release, linking the lamprey peptide to gut-brain appetite suppression.
Why it’s plausible
MC4R is expressed on colonic enteroendocrine L cells and its activation by alpha-MSH increases PYY and GLP-1 secretion in vivo (10.1016/j.cmet.2014.10.004). MSH-B retains the full HFRW pharmacophore and the Boltz-2 prediction strongly supports MC4R engagement (iptm 0.944). If MSH-B's potency advantage over alpha-MSH extends to mammalian MC4R, its L-cell activation would trigger proportionally greater incretin and satiety peptide release. This is mechanistically distinct from the hypothalamic MC4R pathway targeted by setmelanotide, and would represent a peripheral appetite-suppression axis.
Why it matters
A peptide that drives gut-origin satiety signaling via MC4R-L cell coupling would have a differentiated mechanism from existing MC4R agonists focused on central pathways, and could form the basis of peripherally restricted obesity therapeutics with a reduced central nervous system side-effect profile.
Plausibility.38
Novelty.47
Impact.60
Basis · grounding2 papers · 1 computed/note
[1]
paper
MC4R expression on enteroendocrine L cells confirmed; alpha-MSH drives PYY and GLP-1 release in vivo via this pathway
doi: 10.1016/j.cmet.2014.10.004
[2]
structureBoltz-2 iptm 0.944 supports high-confidence MC4R binding geometry
[3]
paper
RM-493 MC4R agonism increases resting energy expenditure in obese humans, establishing MC4R activation as a metabolically significant pathway
doi: 10.1210/jc.2014-4024
openupdated 2026-06-05

If you clip both ends of a chain-shaped molecule together so it holds a fixed shape, does it work better?

Ring-shaped (cyclic) versions of related peptides have historically been around 100 times more potent than the straight-chain versions. If this lamprey peptide, which is already about 10 times more active than the natural human equivalent, could be cyclised, the combined gain might produce a molecule active at extremely low doses. That matters for anyone developing treatments for obesity or skin-pigmentation disorders, where minimizing the dose reduces the risk of side effects.

The hypothesis
Cyclisation of MSH-B via a lactam bridge between the N-terminal valine (V1) and the lysine-equivalent position introduced at the C-terminal region would lock the HFRW core in an active helical conformation and increase MC4R agonist potency by an additional order of magnitude beyond the linear peptide, based on precedent from MT-II-class cyclic melanocortin analogs.
Why it’s plausible
Cyclic melanocortin analogs such as MT-II achieve sub-nanomolar MC4R potency by constraining the HFRW pharmacophore in a beta-turn conformation, a gain of roughly 100-fold over alpha-MSH (10.1034/j.1399-3011.2003.00087.x). MSH-B is already 10-fold more potent than alpha-MSH in the linear form, suggesting its extended N-terminal sequence may partly pre-organise the core. A designed lactam bridge across the N-terminus (adding a lysine at one terminus) would enforce the beta-turn without losing the N-terminal contacts contributed by Y8 and R9, potentially stacking the two potency-enhancing features. The C-terminal amidation already present on MSH-B is one of the two modifications used in MT-II engineering.
Why it matters
If the hypothesis holds, a cyclic MSH-B derivative would represent the most potent melanocortin agonist scaffold derived from a natural non-mammalian sequence, combining the intrinsic potency advantage of the lamprey extension with the conformational gain of cyclisation, and would be a lead compound for obesity or pigmentation-disorder therapeutics.
Plausibility.42
Novelty.38
Impact.60
Basis · grounding1 paper · 2 computed/notes
[1]
paper
Lactam-bridged cyclic analogs of MT-II achieve sub-nanomolar MC4R potency through HFRW core conformational constraint; C-terminal amidation is a shared feature
doi: 10.1034/j.1399-3011.2003.00087.x
[2]
noteC-terminal amidation confirmed; MSH-B linear potency already ~10-fold above alpha-MSH
[3]
sequenceV1 at N-terminus and the backbone geometry of VQESADGYRM provide an N-terminal anchor compatible with lactam bridge engineering analogous to MT-II
openupdated 2026-06-05

Could a molecule known for controlling skin pigmentation also quiet down the immune response in inflamed tissue?

Related peptides from the same family are known to dial back immune overactivation in conditions like inflammatory bowel disease. If this lamprey peptide shares that anti-inflammatory ability through the MC3R receptor, it could be useful for people with chronic inflammatory conditions, and its unusual non-mammalian structure gives chemists a fresh scaffold to build more selective drugs from.

The hypothesis
MSH-B has anti-inflammatory activity in non-ocular mucosal tissues mediated through MC3R, independent of its melanotropin activity, because its HFRW core satisfies the pharmacophoric requirements for MC3R engagement documented for the KPV fragment and related melanocortin anti-inflammatory peptides.
Why it’s plausible
The alpha-MSH C-terminal tripeptide KPV (which MSH-B does not contain) and the intact alpha-MSH sequence both suppress neutrophil infiltration and KC cytokine levels via MC3R (10.1124/jpet.103.051623). MSH-B carries the complete HFRW core that is required for MC3R binding; MC3R recognises this motif across melanocortin peptides (10.1016/j.molmet.2021.101206). MSH-B's N-terminal extension is amphipathic (charged residues E3, D6, R9) and could mediate additional interactions with MC3R extracellular loops. The anti-inflammatory melanocortin pathway is relevant to inflammatory bowel disease, uveitis (10.3109/09273948.2015.1092560), and gouty arthritis contexts mentioned in the reference set.
Why it matters
Establishing MC3R-mediated anti-inflammatory activity for MSH-B would expand its therapeutic potential beyond pigmentation and obesity into inflammatory disease, and its non-mammalian origin means it represents a structurally novel scaffold for developing MC3R-biased anti-inflammatory melanocortins.
Plausibility.39
Novelty.40
Impact.57
Basis · grounding2 papers · 1 computed/note
[1]
paper
MC3R drives anti-inflammatory effects of melanocortin peptides including suppression of PMN infiltration; HFRW core is the minimal pharmacophore
doi: 10.1124/jpet.103.051623
[2]
paper
Binding affinity table confirms MC3R recognises the melanocortin HFRW motif across natural and synthetic analogs
doi: 10.1016/j.molmet.2021.101206
[3]
sequenceHFRW confirmed at positions 12-15; KPV motif is absent, meaning any MC3R anti-inflammatory activity is HFRW-core-driven rather than KPV-mediated
openupdated 2026-06-05

Could one specific building block in a 19-piece molecule be responsible for most of its extra strength?

Pinpointing which piece of a peptide drives its potency lets chemists build shorter, simpler drug-like molecules that keep the benefit and drop the rest. If tyrosine at position 8 turns out to be the key contact point, it could guide the design of compact, stable analogs useful as obesity or pigmentation-disorder treatments, potentially with better manufacturing economics than larger peptides.

The hypothesis
The tyrosine residue at position 8 (Y8, within the VQESADGY segment) forms an additional pharmacophoric contact at the melanocortin receptor binding pocket that is responsible for MSH-B's approximately 10-fold potency advantage over alpha-MSH.
Why it’s plausible
Alpha-MSH contains no tyrosine in an equivalent position relative to the HFRW core; its potency-relevant residues are primarily the HFRW core and the N-terminal serine acetylation. MSH-B's sequence VQESADGYRM places a tyrosine (Y8) four residues N-terminal to the core methionine (M10) and arginine (R9), creating a YRM triad that could pre-organise the peptide backbone or contribute a direct aromatic contact to extracellular loop 2 of MC receptors, a known allosteric hotspot in melanocortin GPCR pharmacology. Structural studies on cyclic melanocortin analogs (10.1034/j.1399-3011.2003.00087.x) demonstrate that ring-constrained analogues with aromatic residues outside the HFRW core achieve substantially altered potency and selectivity.
Why it matters
Identifying Y8 as a potency-determining residue would provide the structural rationale for MSH-B's superior bioassay activity and would guide minimal-motif truncation analogs, potentially yielding shorter, more drug-like MC-receptor agonists with the same potency advantage.
Plausibility.37
Novelty.47
Impact.53
Basis · grounding1 paper · 2 computed/notes
[1]
sequenceY8 confirmed present in VQESADGYRMQHFRWGQPLP; positioned four residues N-terminal to the HFRW-adjacent methionine
[2]
paper
SAR studies on MT-II/SHU-9119 lactam derivatives show aromatic residues outside the core shift MC3R/MC4R/MC5R potency independently of HFRW
doi: 10.1034/j.1399-3011.2003.00087.x
[3]
noteStructural basis of ~10-fold potency over alpha-MSH explicitly listed as unexplained open question
details expand to inspect
full evidence table2 metrics
metricvaluetool
ipTM 0.9444080591201782 boltz-2
ranking score 0.8346496820449829 boltz-2
structural qualityopenfold3
metricvaluenote
gpde0.569global PDE — lower = better
disorderNaNfraction disordered
3-letter notation
Val-Gln-Glu-Ser-Ala-Asp-Gly-Tyr-Arg-Met-Gln-His-Phe-Arg-Trp-Gly-Gln-Pro-Leu-Pro
recipeboltz-2 1.0
parametervalue
modelboltz-2 1.0
weights
hardwarenvidia_nim_api
mlx version
python
random seed
msa strategynone
diffusion samples1
runtime
predicted bymlx@peptide
predicted at2026-04-24
citationbibtex
peptidemodel (2026). Skin-pigmentation research peptide (MSH-B) (pep-10681, v1). PeptideModel. https://peptidemodel.com/card/pep-10681
@peptide{pep10681,
  sequence = {VQESADGYRMQHFRWGQPLP},
  target   = {mc4r},
  author   = {peptidemodel},
  year     = {2026},
  status   = {bioassayed}
}
related peptides 3 by signal overlap
clinical trials 2 on ct.gov · checked 2026-05-09
ct.gov trials 2
by phase
2no phase
by status
2completed
references 9 papers
[1] supporting
[6] supporting
[9] supporting
discussion no comments
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peptidemodel.com CC-BY-SA-4.0 research only · not for human use