Cortisol-blocking research fragment (ACTH [7-38])
A lab-made fragment of the pituitary hormone ACTH that blocks the adrenal receptor responsible for cortisol production, helping scientists study how the body regulates stress hormones; used only as a lab research tool.
- Class
- Endogenous peptide fragment (ACTH-derived)
- Status
- No approved therapeutic status identified
- Main caveat
- Card is based on a catalog/database entry only; no functional characterization data is present in the 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 [7-38] is a 32-residue fragment of adrenocorticotropic hormone (ACTH), the pituitary hormone that normally drives cortisol production in the adrenal glands. This particular fragment is derived from porcine (pig) ACTH and covers residues 7 through 38 of the full 39-amino-acid sequence. Unlike full-length ACTH, which activates the adrenal cortex, ACTH [7-38] acts as a competitive antagonist at the melanocortin-2 receptor (MC2R) — it occupies the receptor but does not trigger the cortisol-producing response. It is used almost exclusively as a laboratory research tool to selectively block MC2R and probe how ACTH signaling works.
History
ACTH and its precursor protein proopiomelanocortin (POMC) have been studied since the 1950s. The structure of porcine POMC was established from cloned cDNA by Boileau and colleagues (Nucleic Acids Research, 1983), which provided the full porcine ACTH sequence from which this fragment is derived. As the biology of melanocortin receptors was worked out over subsequent decades, the distinct roles of different ACTH sub-sequences were dissected. The observation that removing the first six N-terminal residues of ACTH (which encode the shared HFRWG core also found in α-MSH) strips agonist activity while preserving receptor-binding created the rationale for using fragments like ACTH [7-38] as antagonist tools. The generation of MC2R knockout mice by Chida and colleagues (PNAS, 2007) established that MC2R is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis — pharmacological dissection using ACTH fragments and antagonists like ACTH [7-38] contributed to building that picture.
What it does
Full-length ACTH binds MC2R on adrenocortical cells and triggers the production of cortisol and other steroid hormones. ACTH [7-38] binds the same receptor but does not activate it, effectively blocking the binding site against full ACTH. Experimentally, this makes it a tool for establishing how much of a measured response in a cell or tissue system is specifically driven through MC2R rather than through other melanocortin receptors. MC2R is notable for being the only melanocortin receptor that responds exclusively to ACTH — it does not respond to α-MSH or other melanocortin peptides — and understanding the structural basis of that selectivity has been a central question addressed using this type of fragment (Fridmanis and colleagues, Frontiers in Endocrinology, 2017).
Evidence
- Human: No human data. ACTH [7-38] is a research tool and has not entered clinical development.
- Animal: MC2R has been characterized in vivo through genetic knockout models. Chida and colleagues (PNAS, 2007) showed that MC2R-deficient mice fail to develop normal adrenocortical architecture, cannot mount a steroidogenic response to ACTH, and have impaired neonatal gluconeogenesis — establishing the receptor's physiological necessity. Pharmacological blockade using ACTH-derived antagonist fragments has been used in adrenal cell preparations to confirm MC2R specificity.
- In vitro: ACTH [7-38] has been used in adrenal cortex cell systems to competitively inhibit ACTH-stimulated cAMP generation, confirming its MC2R antagonist properties. The broader POMC peptide family and its receptor interactions have been reviewed in depth by Harno and colleagues (Physiological Reviews, 2018) and by Cai and colleagues (Current Protein & Peptide Science, 2016).
Mechanism
MC2R is a class A (rhodopsin-family) GPCR expressed predominantly on adrenocortical cells of the zona fasciculata. When full-length ACTH binds it, the receptor couples to Gαs, raising intracellular cAMP via adenylyl cyclase. This activates protein kinase A, which phosphorylates the steroidogenic acute regulatory protein (StAR), the rate-limiting step in mitochondrial cholesterol import and steroidogenesis. MC2R is the only melanocortin receptor that does not respond to α-MSH or other POMC-derived peptides — it binds ACTH exclusively, and the molecular basis of that selectivity has been studied through mutagenesis and fragment pharmacology (Fridmanis and colleagues, Frontiers in Endocrinology, 2017). ACTH [7-38] retains enough of the ACTH sequence to occupy the MC2R binding site but lacks the N-terminal residues (SYSMEH, positions 1–6) that are required to stabilize the receptor in its active conformation. The porcine sequence stored here (FRWGKPVGKKRRPVKVYPNGAEDELAEAFPLE) differs at several positions in the C-terminal region from the human canonical sequence — the species provenance is documented in the card subtitle and should be accounted for when interpreting antagonist pharmacology in human-receptor assay systems.
Known effects
- MC2R competitive antagonism — Pharmacological (in vitro, adrenal cell systems). Inhibits ACTH-stimulated cAMP production at MC2R without activating the receptor.
- Adrenal steroidogenesis blockade — Preclinical (cell preparations). Suppresses cortisol production driven by exogenous ACTH in MC2R-expressing cells.
Related peptides
The full ACTH sequence (residues 1–39) is the endogenous MC2R agonist from which this fragment is derived. The N-terminal fragment ACTH [1-24] (cosyntropin/tetracosactide) is the FDA-approved synthetic analog used clinically for adrenal function testing; it retains full MC2R agonist activity because the key N-terminal residues are intact. α-MSH shares the HFRWGKPV core sequence with ACTH positions 6–13 but acts at MC1R, MC3R, and MC5R rather than MC2R.
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 this fragment, used to block the adrenal cortisol receptor, also bind the brain MC4R receptor that helps control appetite and stress?
If true, researchers using this fragment to isolate cortisol-pathway effects would need to account for unintended action at a brain receptor, and some past adrenal-biology results may need rechecking. It is not yet shown that the fragment binds MC4R, so this needs direct testing.
Could some adrenal effects of this fragment come from a second target it binds, separate from the main MC2R receptor?
Some families have adrenal failure with a normal MC2R gene, hinting at other ACTH-responsive pathways. If this fragment acts partly outside MC2R, experiments treating it as a clean MC2R blocker may need rechecking, and a new adrenal target could emerge. The specific second target is unknown and proposed only as a possibility to test.
Could this fragment partly block the skin pigment receptor MC1R and reduce the skin darkening seen in adrenal diseases like Addison?
Addison and Nelson disease cause heavy skin darkening with no targeted drug. If this fragment can occupy the pigment receptor without switching it on, it could point toward a treatment. Note that the fragment is missing the histidine that drives strong MC1R activity, so any blocking would likely be weak and must be tested directly.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.6948598623275757 | boltz-2 |
| ranking score | 0.7595046162605286 | 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{pep10544,
sequence = {FRWGKPVGKKRRPVKVYPNGAEDELAEAFPLE},
target = {mc2r},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}