Shark adrenal-signaling peptide (alpha-MSH II from spiny dogfish)
A natural hormone fragment from dogfish shark that targets the adrenal gland's stress-hormone receptor; used only as a lab research tool to study how this receptor evolved across animals.
- Class
- Endogenous neuropeptide (fish-derived MSH variant)
- Status
- No approved therapeutic status identified
- Best-supported effect
- Identity established by purification and sequencing from spiny dogfish (Squalus acanthias) pituitary; no functional bioactivity data attached to this card
- Main caveat
- This card is based on a single 1970 purification and sequencing report; no assay, animal, or human evidence is attached
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
The alpha-Melanocyte Stimulating Hormone II peptide (α-MSH II) from the spiny dogfish (Squalus acanthias) is a naturally occurring 12-amino-acid fragment derived from the pituitary POMC precursor protein of an elasmobranch fish. It belongs to the melanocortin peptide family — a group of hormones that includes ACTH and the various MSH peptides, all cut from the same large precursor. Researchers use this peptide to study the pharmacology of the melanocortin 2 receptor (MC2R), the adrenal-cortex receptor that normally responds only to ACTH, and to explore how receptor selectivity for ACTH evolved across vertebrates.
History
The spiny dogfish pituitary was a productive source for early peptide hormone research because the intermediate lobe of the gland is exceptionally large and yields substantial quantities of melanotropins. In 1970, Lowry and colleagues purified and sequenced a melanocyte-stimulating hormone from dogfish pituitary extracts, reporting a core 11-residue sequence (Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Met) and noting that about one fifth of isolated molecules carried an additional N-terminal tyrosine, giving rise to the 12-residue form now cataloged here as α-MSH II (Lowry et al., 1970). They also found that roughly half the molecules had a free C-terminal carboxyl group while the other half were C-terminally amidated — a difference that distinguishes α-MSH II (free carboxyl, Tyr-extended) from α-MSH I (amidated, shorter). Follow-up structural work by Bennett, Lowry and McMartin (1974) established that the N-terminal 13 residues of dogfish ACTH are identical to dogfish α-MSH, confirming ACTH as its biosynthetic precursor in the pars distalis. Eberle and colleagues (1978) then chemically synthesized both dogfish α-melanotropin I and II and tested a series of analogs, demonstrating that removal of the N-terminal acetyl group strongly reduces melanotropic potency and that substitution at the C-terminus (amide vs. free acid) has comparatively modest effects.
What it does
In a research setting, α-MSH II from dogfish is used as a pharmacological probe at MC2R — the receptor responsible for driving glucocorticoid production in the adrenal cortex. Unlike ACTH, α-MSH peptides naturally lack the tetrabasic "address" sequence (Lys-Lys-Arg-Arg) that mammalian and most bony-vertebrate MC2R orthologs require for full activation; α-MSH II therefore binds the receptor but activates it with dramatically lower potency than the intact ACTH molecule (Fridmanis et al., 2017). Studies on the closely related Pacific spiny dogfish MC2R showed approximately 1000-fold greater sensitivity to ACTH(1-24) compared with α-MSH-sized ligands. This selectivity gap makes the dogfish peptide a useful tool for separating the contributions of the shared HFRW "message" motif from the KKRR "address" motif in receptor activation experiments.
Evidence
- Human: No human studies. This peptide is a non-human research tool, not a clinical compound.
- Animal / in vitro: Used in receptor pharmacology experiments to probe MC2R activation. The Squalus acanthias pituitary was the original biological source; receptor assays in transfected cell lines have compared its potency to ACTH and other melanocortin ligands. Eberle and colleagues (1978) reported melanocyte-dispersing bioactay data for synthetic α-MSH I, α-MSH II, and analogs, confirming the structural assignments made by Lowry and colleagues. No registered trials on ClinicalTrials.gov for "alpha-melanocyte stimulating hormone II."
Mechanism
MC2R (the ACTH receptor) is a class A GPCR expressed almost exclusively in the zona fasciculata of the adrenal cortex, where it drives steroidogenesis via Gαs → cAMP → PKA signaling. All five melanocortin receptors share the His-Phe-Arg-Trp (HFRW) core pharmacophore, which is present in ACTH, α-MSH, β-MSH, γ-MSH, and δ-MSH. What makes MC2R unique is that it additionally requires the basic Lys-Lys-Arg-Arg "address" motif found only in ACTH (residues 15–18) for high-potency activation; without it, HFRW-containing peptides like α-MSH II can engage the receptor but fail to activate it efficiently in bony-vertebrate orthologs (Fridmanis et al., 2017). MC2R cannot reach the cell surface without co-expression of the melanocortin receptor accessory protein MRAP1, a single-transmembrane protein that facilitates receptor trafficking from the endoplasmic reticulum and enhances ACTH recognition (Hinkle et al., 2009). Loss-of-function mutations in either MC2R or MRAP cause familial glucocorticoid deficiency (FGD), an inherited inability to produce cortisol in response to ACTH. The raw sequence stored here (YSMEHFRWGKPM) is the free-acid form (α-MSH II); the biologically related α-MSH I has one fewer residue at the N-terminus and a C-terminal amide rather than a free carboxyl group — modifications that are absent from the stored 1-letter sequence but are relevant to potency comparisons (Eberle et al., 1978).
Known effects
- Melanocyte stimulation (in vitro / frog/lizard bioassay) — melanocyte-dispersing activity confirmed for synthetic dogfish α-MSH I and II; substantially weaker than N-terminally acetylated mammalian α-MSH (Eberle et al., 1978) — Preclinical only
- MC2R partial activation — dogfish MSH-sized ligands engage elasmobranch MC2R with 100–1000-fold lower potency than ACTH(1-24); useful as a pharmacological control — Mechanistic/in vitro only
- POMC processing research tool — used to characterize tissue-specific cleavage patterns in pituitary intermediate vs. anterior lobes (Lowry et al., 1970; Bennett et al., 1974; Harno et al., 2018) — Experimental
Regulatory status
- US / EU: Not a regulated pharmaceutical; no INN. Research reagent only.
- WADA: Not listed on the WADA prohibited list (peptide hormone fragments without established performance-related effect).
Related peptides
The melanocortin family shares the HFRW pharmacophore and POMC precursor origin. Related cards on this platform include α-MSH and ACTH-derived peptides that act at overlapping receptor sets. For the receptor context, see the MC2R-targeting ACTH family; for broader melanocortin pharmacology including MC4R and energy balance, see the melanocortin receptor system review cards (Ericson et al., 2017; Cai et al., 2016; Prindle et al., 2026).
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.
Could the body's stress-hormone switch be set to "picky" by a helper protein, not just by the receptor it plugs into?
If this holds, a protein called MRAP1 acts as a selectivity filter, deciding which signals are allowed through, not just a delivery vehicle. That could open a path to drugs that tweak this filter and help people with adrenal insufficiency respond to their own hormones again, instead of relying on hormone replacement.
Why do human adrenal receptors demand a very specific hormone signal when shark versions work with a simpler one?
If this structural difference is confirmed, researchers would know the exact molecular feature that makes human cortisol receptors so selective. That knowledge could guide the design of smaller, simpler hormone-like drugs for familial glucocorticoid deficiency, a rare condition where the adrenal gland ignores its normal hormonal trigger.
What if a hormone discovered in sharks is binding most tightly to a skin and immune receptor, not the stress-response receptor scientists assumed?
If MC1R turns out to be the real target, the whole story of why sharks process this hormone would need rewriting: it might be about color or immunity, not cortisol. For drug developers, it would also clarify where this peptide actually works, avoiding wasted effort chasing the wrong receptor.
Could a peptide from shark hormones quiet runaway brain immune cells, independently of the stress-hormone system?
If this pans out, even a raw, unmodified version of this peptide might dial down the kind of chronic brain inflammation linked to conditions like Alzheimer's or Parkinson's. It would also show that a simpler, shorter hormone fragment, without the chemical tweaks usually needed for potency, might still be enough to do useful anti-inflammatory work.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.8795090913772583 | boltz-2 |
| ranking score | 0.8664582371711731 | boltz-2 |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.451 | global PDE — lower = better |
| disorder | NaN | fraction disordered |
▸3-letter notation
▸recipeboltz-2 1.0
| parameter | value |
|---|---|
| model | boltz-2 1.0 |
| weights | — |
| hardware | nvidia_nim_api |
| mlx version | — |
| python | — |
| random seed | — |
| msa strategy | none |
| diffusion samples | 1 |
| runtime | — |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
▸citationbibtex
@peptide{pep10718,
sequence = {YSMEHFRWGKPM},
target = {mc2r},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}