Cortisol-trigger hormone fragment (ACTH [1-31])
A lab-made piece of the pituitary hormone that tells the adrenal glands to make cortisol; used only as a lab research tool to study how that signal works.
- Class
- Endogenous peptide fragment (ACTH N-terminal fragment; POMC-derived)
- Status
- No approved therapeutic status identified
- Main caveat
- Catalog source only; no biological activity, clinical, or animal evidence is attached to this card's source file
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
ACTH [1-31] is the first 31 amino acids of adrenocorticotropic hormone (ACTH), the pituitary hormone that tells the adrenal glands to produce cortisol. This card covers the synthetic fragment based on the porcine ACTH sequence, which differs from the full-length 39-residue human hormone at its C-terminus. The sequence stored here — SYSMEHFRWGKPVGKKRRPVKVYPNGAEDEL — represents the biologically active core of ACTH that contains both the MC2R-binding determinants and the HFRWG motif shared with alpha-melanocyte-stimulating hormone (α-MSH). Researchers use this fragment to probe MC2R receptor specificity and to dissect which parts of the ACTH sequence drive adrenocortical versus melanocortin signaling.
History
ACTH as a hormone was isolated and sequenced in the 1950s. Its full precursor, proopiomelanocortin (POMC), was later characterized at the gene and mRNA level — Boileau and colleagues (1983) published the complete structure of the porcine POMC mRNA from cloned cDNA, establishing the exact sequence context from which ACTH [1-31] is derived. The porcine sequence has been widely used in biochemical work on ACTH because porcine and human ACTH share nearly identical N-terminal residues through the biologically active region, making porcine-derived fragments useful experimental tools. Interest in defined fragments of ACTH grew alongside the broader melanocortin receptor field: as MC1R, MC2R, MC3R, MC4R, and MC5R were cloned and deorphanized in the early 1990s, the need for precise subtype-selective peptide probes increased, and fragments covering different portions of the ACTH sequence became important research tools for mapping receptor binding requirements (Fridmanis and colleagues, 2017).
What it does
ACTH [1-31] binds the melanocortin 2 receptor (MC2R), the GPCR that is essentially exclusive to the adrenal cortex among the five melanocortin receptor subtypes. When MC2R is activated, adrenocortical cells increase production of cortisol and, to a lesser extent, adrenal androgens. Chida and colleagues (2007) demonstrated in MC2R-knockout mice that MC2R is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis — establishing how central this receptor-ligand axis is to normal adrenal function. Beyond MC2R, the N-terminal HFRWG motif within ACTH [1-31] overlaps with the core binding sequence of α-MSH and can interact with other melanocortin receptors (MC1R, MC3R, MC5R), though these interactions are generally weaker than the dedicated high-affinity MC2R engagement (Fridmanis and colleagues, 2017). The broader POMC-derived peptide system and its physiological roles — spanning energy balance, stress response, pigmentation, and immune modulation — are reviewed in depth by Harno and colleagues (2018).
Evidence
- Human: No clinical trials for ACTH [1-31] specifically as an isolated fragment. The clinical evidence base belongs to the full 39-residue hormone and the synthetic 1-24 fragment (cosyntropin); ACTH [1-31] is used as a research tool rather than a clinical agent.
- Animal: MC2R knockout studies (Chida and colleagues, 2007) established the essential role of the ACTH–MC2R axis in adrenal development and steroidogenesis in mice. ACTH physiology across the 1-39 sequence has been characterized in extensive animal work; the 1-31 fragment's specific preclinical profile is largely documented in receptor binding and signaling studies.
- In vitro: ACTH [1-31] and related fragments have been used in cell-based assays to characterize MC2R binding and cAMP signaling. The intracellular signaling mechanisms downstream of melanocortin receptor activation — including Gαs/cAMP/PKA cascades — are reviewed by Rodrigues and colleagues (2015).
Mechanism
MC2R is a class A GPCR coupled to Gαs. When ACTH [1-31] engages MC2R on adrenocortical cells, it stimulates adenylyl cyclase, raising intracellular cAMP and activating protein kinase A. This cascade phosphorylates the steroidogenic acute regulatory protein (StAR), which shuttles cholesterol across the inner mitochondrial membrane — the rate-limiting step of steroidogenesis leading to cortisol synthesis. Fridmanis and colleagues (2017) reviewed the molecular determinants of MC2R specificity in detail, noting that unlike MC1R through MC5R, MC2R does not respond to the short His-Phe-Arg-Trp (HFRW) core motif alone and requires additional residues from the ACTH sequence for full activation, which is why α-MSH and other short melanocortin peptides cannot activate MC2R. The melanocortin receptor system's potential as a target in multiple degenerative and inflammatory diseases — mediated through MC1R and MC3R rather than MC2R — is surveyed by Cai and colleagues (2016). The POMC precursor and the broader logic of how differential tissue-specific processing generates distinct peptide hormones from the same gene is reviewed in Harno and colleagues (2018).
Known effects
- Adrenocortical steroidogenesis stimulation — Mechanistic (MC2R activation drives cortisol synthesis; well-established from ACTH biology)
- MC2R receptor agonism — Mechanistic only (in vitro and animal studies; no clinical data for the 1-31 fragment specifically)
Safety signals
No clinical safety data exist for ACTH [1-31] as a standalone research peptide in humans. The safety profile of therapeutic ACTH preparations relates to the full-length hormone or the cosyntropin (1-24) fragment, not to the 1-31 fragment specifically.
Regulatory status
- US: ACTH [1-31] as an isolated synthetic fragment has no FDA regulatory status; it is not an approved drug. The related clinical agents — cosyntropin (ACTH 1-24) and repository corticotropin injection (Acthar Gel) — are FDA-approved prescription products.
- Research use: ACTH [1-31] is available as a research-grade synthetic peptide for laboratory use.
- WADA: Corticotropins are prohibited under WADA's S9 class; athletes subject to the WADA code should be aware that ACTH-related peptides fall under that prohibition.
Related peptides
- Alpha-MSH — Shares the N-terminal SYSMEHFRWG core with ACTH [1-31] but carries an N-terminal acetyl cap and C-terminal amide modification; acts at MC1R and MC3R rather than MC2R.
- ACTH (full-length, 1-39) — The complete 39-residue hormone; cosyntropin (1-24) is the FDA-approved synthetic fragment used diagnostically.
- Melanocortin peptides (MC3R/MC4R ligands) — Share the HFRWG pharmacophore but differ in receptor subtype selectivity.
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 attaching a PEG polymer at lysine-16 of ACTH(1-31) make it last longer in the body without losing its ability to stimulate the adrenal gland?
If successful, this could produce a fully synthetic, precisely defined drug to replace a controversial animal-derived product that currently costs tens of thousands of dollars per vial. Patients with infantile spasms, kidney disease, or multiple sclerosis who rely on this therapy could benefit from a more consistent, affordable, and ethically sourced treatment.
Does swapping proline for alanine at position 24 of ACTH change which stress hormone the adrenal gland makes in response?
If this single swap redirects steroid output, it could lead to a precisely targeted treatment for patients who are deficient specifically in aldosterone, the hormone that regulates salt and blood pressure, without accidentally over-stimulating cortisol and causing the side effects associated with steroid therapy.
Does ACTH(1-31) activate a different internal signaling pathway in adrenal cells than the shorter ACTH(1-17) fragment?
If ACTH(1-31) triggers a separate signaling branch that controls inflammation without releasing a large cortisol surge, it could be developed into an anti-inflammatory drug that avoids many of the serious side effects associated with current cortisol-based treatments, helping patients with autoimmune diseases, multiple sclerosis, or infantile spasms.
Is ACTH(1-31) better at docking to and activating the adrenal cortisol receptor than the full 39-amino-acid hormone?
If the shorter form is more potent at the adrenal receptor, it could replace or improve upon current ACTH-based therapies used for adrenal insufficiency and inflammatory conditions, offering cleaner pharmacology with less off-target variability.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.7730052471160889 | boltz-2 |
| ranking score | 0.7720047831535339 | boltz-2 |
▸3-letter notation
▸recipeboltz-2 2.2.1
| parameter | value |
|---|---|
| model | boltz-2 2.2.1 |
| weights | — |
| hardware | vast_v100_32gb |
| mlx version | — |
| python | — |
| random seed | 1 |
| msa strategy | colabfold_local |
| runtime | — |
| predicted by | — |
| predicted at | 2026-05-22 |
▸citationbibtex
@peptide{pep10668,
sequence = {SYSMEHFRWGKPVGKKRRPVKVYPNGAEDEL},
target = {mc2r},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}