ACTH stress-hormone signal (38-amino-acid form)
A near-complete form of the pituitary hormone that tells the adrenal glands to make cortisol, the body's main stress hormone; used only as a lab research tool.
- Class
- Peptide fragment derived from the ACTH/β-lipotropin precursor
- Status
- No approved therapeutic status identified
- Main caveat
- This card describes a sequence-identified bovine-derived peptide fragment; no bioactivity, efficacy, or safety data are 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
Adrenocorticotropic hormone (ACTH) is a peptide hormone released by the pituitary gland that tells the adrenal glands to produce cortisol — the body's main stress hormone. This card covers the 38-residue form, ACTH [1-38], which spans all but the final amino acid of the canonical 39-residue sequence. ACTH is an endogenous hormone encoded within a larger precursor protein called proopiomelanocortin (POMC), from which it is cleaved along with several other biologically active peptides (Harno et al., Physiological Reviews, 2018). Two synthetic forms of ACTH have medical use: cosyntropin (the first 24 residues, also called tetracosactide), used to test adrenal gland function; and repository corticotropin injection (Acthar Gel), a long-acting porcine-derived formulation used therapeutically in a narrow set of inflammatory and neurologic conditions.
History
The molecular origins of ACTH were established when Nakanishi and colleagues (Nature, 1979) cloned and sequenced the bovine cDNA encoding the full POMC precursor, revealing that ACTH, β-lipotropin, and α-MSH all arise from the same polyprotein by tissue-specific proteolytic processing. This confirmed ACTH's place in a family of melanocortin peptides sharing the N-terminal HFRW core that drives MC2R binding. The receptor specificity of ACTH at MC2R — and what distinguishes MC2R from the other four melanocortin receptors — has been the subject of sustained structural investigation; Fridmanis and colleagues (Frontiers in Endocrinology, 2017) reviewed the molecular determinants that make MC2R uniquely selective for ACTH compared with the broader melanocortin family.
What it does
ACTH is the principal hormonal driver of cortisol synthesis in the adrenal cortex. When ACTH reaches the adrenal glands, it binds the melanocortin 2 receptor (MC2R), triggering a signaling cascade that ultimately mobilizes cholesterol into the steroidogenesis pathway and drives cortisol production. Chida and colleagues (PNAS, 2007) demonstrated the essentiality of this pathway by generating MC2R-knockout mice, which showed severely impaired adrenal development, failed steroidogenesis, and neonatal metabolic defects — confirming that MC2R signaling is required for normal adrenocortical function. Because ACTH shares its N-terminal sequence with α-melanocyte-stimulating hormone and has some affinity for other melanocortin receptors (MC1R, MC3R, MC5R), research has explored whether ACTH's effects in inflammatory disease may partly involve direct receptor signaling on immune cells beyond the cortisol-mediated pathway (Cai et al., Current Protein & Peptide Science, 2016).
Evidence
- Human: Cosyntropin (ACTH 1-24) has extensive clinical validation as the standard diagnostic agent for assessing adrenal reserve. Repository corticotropin injection (Acthar Gel, full-length ACTH) has randomized controlled trial support for infantile spasms and has been used in acute multiple sclerosis relapses and nephrotic syndrome, though the evidence base for non-infantile-spasms indications is variable. The peptidelist catalog (ACTH entry, April 2026) characterizes the overall human evidence grade as Strong for diagnostic use and infantile spasms.
- Animal: MC2R knockout studies in mice have been central to characterizing the role of ACTH signaling in adrenal development and gluconeogenesis (Chida et al., PNAS, 2007). Extensive earlier animal work established the HPA-axis physiology underlying ACTH's action.
- In vitro / mechanistic: The intracellular signaling cascade downstream of MC2R — Gαs coupling, cAMP elevation, protein kinase A activation — has been characterized in detail; Rodrigues and colleagues (Cellular and Molecular Life Sciences, 2015) reviewed the current state of melanocortin receptor intracellular signaling across all five receptor subtypes.
Known effects
- Cortisol synthesis stimulation — Established physiology; MC2R-mediated cAMP/PKA/StAR pathway drives adrenocortical steroidogenesis (Chida et al., PNAS, 2007; Rodrigues et al., Cellular and Molecular Life Sciences, 2015)
- Adrenal gland maintenance — Chronic ACTH stimulation sustains adrenocortical mass; MC2R knockout leads to adrenal hypoplasia (Chida et al., PNAS, 2007)
- Anti-inflammatory effects (indirect and possibly direct) — Cortisol elevation accounts for most observed anti-inflammatory effects; a possible additional contribution from MC1R/MC3R signaling on leukocytes is hypothesized but not definitively established in clinical populations (Cai et al., Current Protein & Peptide Science, 2016)
Safety signals
ACTH's safety profile in clinical use reflects the downstream effects of sustained cortisol elevation, which closely parallel those of systemic glucocorticoid therapy. Prolonged ACTH exposure can produce fluid retention, hyperglycemia, hypertension, hypokalemia, mood changes, and, with chronic high-dose use, Cushingoid features and adrenal suppression on withdrawal. Because MC2R activation drives the HPA axis, the risk of adrenal suppression after discontinuing a sustained ACTH course is analogous to recovery following systemic corticosteroid therapy. Hypersensitivity reactions, including anaphylaxis, have been reported with animal-derived repository corticotropin formulations.
Regulatory status
- US: Cosyntropin (synthetic ACTH 1-24) and repository corticotropin injection (Acthar Gel) are FDA-approved prescription medications. ACTH is not available over the counter and is not part of the compounded-peptide market.
- EU/International: Tetracosactide (cosyntropin), sold as Synacthen in many markets, is approved across the EU, UK, Canada, Australia, and most major markets as a prescription diagnostic agent.
- WADA: Corticotropins are prohibited under WADA's S9 class (Glucocorticoids), which covers agents stimulating endogenous glucocorticoid production. Tetracosactide is named specifically in WADA technical documents. Athletes subject to WADA rules require a therapeutic use exemption for medically indicated use.
Mechanism
ACTH is cleaved from POMC in corticotroph cells of the anterior pituitary. The POMC precursor encodes ACTH along with other melanocortin peptides and opioid precursors; tissue-specific processing determines which fragments are released, a variability comprehensively reviewed by Harno and colleagues (Physiological Reviews, 2018). ACTH binds MC2R, a Gs-coupled receptor expressed predominantly on cells of the adrenal zona fasciculata. MC2R is unique among the five melanocortin receptors in being selective for ACTH — the molecular determinants of this selectivity, including residues in the extracellular loops that distinguish MC2R from the more promiscuous MC1R, MC3R, MC4R, and MC5R, have been analyzed by Fridmanis and colleagues (Frontiers in Endocrinology, 2017). MC2R activation raises intracellular cAMP and activates protein kinase A, which phosphorylates the steroidogenic acute regulatory protein (StAR), enabling cholesterol import into the mitochondrial matrix — the rate-limiting step of steroidogenesis. This drives synthesis of cortisol (zona fasciculata) and, to a lesser extent, adrenal androgens (zona reticularis). Chronic ACTH stimulation causes adrenocortical hyperplasia. The broader melanocortin receptor family, its mutations, and phenotypic consequences across species have been characterized by Switonski and colleagues (Journal of Applied Genetics, 2013) and Cai and colleagues (Current Protein & Peptide Science, 2016).
The [1-38] form stored in this card is one residue shorter than the full canonical 39-residue hormone; the biological significance of this C-terminal truncation has not been separately characterized from the full-length peptide in the available literature.
Open questions
- Whether ACTH's observed anti-inflammatory effects in conditions such as infantile spasms and MS relapses are wholly cortisol-mediated or include a distinguishable direct contribution from MC1R/MC3R signaling on leukocytes — the key unresolved question for repository corticotropin's therapeutic rationale.
- Whether the [1-38] truncation compared with full-length ACTH [1-39] produces any measurable difference in MC2R binding affinity, pharmacokinetics, or downstream signaling.
- Optimal cut-off thresholds for the cosyntropin stimulation test using modern liquid chromatography–mass spectrometry cortisol assays, where historical thresholds derived from older immunoassays may require recalibration.
Related peptides
- α-MSH shares ACTH's N-terminal sequence (the first 13 residues) and arises from the same POMC precursor, acting at MC1R rather than MC2R — see the melanocortin family cards for comparison.
- Cosyntropin (ACTH 1-24) is the truncated synthetic form covering the biologically active N-terminal domain; its diagnostic use in the cosyntropin stimulation test rests on the same MC2R binding determinants present in the full ACTH sequence.
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.
Does a short stretch of positively charged building blocks help ACTH stick to the adrenal cell surface first, making it more effective at triggering the cell?
If this docking step turns out to be real, it would explain why short ACTH fragments work far worse than the full hormone in the body even when they bind the receptor just fine in a test tube. For drug designers, it would mean that any synthetic ACTH replacement needs to keep this charged patch, not just the core signaling region.
If you rigidly constrain the shape of ACTH, could it become selective enough for the adrenal receptor that it avoids triggering receptors responsible for cardiovascular and other systemic side effects?
Current ACTH-based treatments hit multiple receptors across the body, causing unwanted effects on blood pressure, appetite, and mood. A conformationally locked version, if it works, could deliver the same adrenal benefit with far fewer systemic problems, and would also give patients a well-defined synthetic option instead of the animal-derived gel product used today.
Could ACTH act directly on brain immune cells to stop infantile spasms, separate from its well-known ability to raise cortisol?
Doctors have long wondered why ACTH controls infantile spasms better than plain steroid drugs, even at equivalent cortisol levels. If a cortisol-independent brain pathway is confirmed, it would justify developing more targeted drugs for these devastating seizures and could open a path to treating other neuroinflammatory conditions without the harms that come with raising cortisol in infants.
Could ACTH act directly on vulnerable brain cells in Parkinson's disease to slow the inflammation that kills them, without involving the adrenal gland at all?
Parkinson's disease has no treatment that actually slows the loss of dopamine neurons. If ACTH can protect those neurons through a receptor found on the neurons themselves, rather than through cortisol, it would point toward a new class of neuroprotective drugs, and the parts of ACTH responsible for adrenal stimulation could potentially be trimmed away, making any future treatment safer for long-term use.
Is there a dose of ACTH low enough to trigger brain-protective signals in the CNS while staying below the level that pumps out cortisol and causes glucocorticoid side effects?
High-dose steroids are actually harmful in traumatic brain injury and are no longer used. If a low-dose ACTH window exists where the drug activates protective pathways in the brain without significantly raising cortisol, it could offer a pharmacological neuroprotectant for a condition that currently has none, and would give researchers a concrete dose range to test in clinical trials.
Does the back end of the ACTH molecule actually touch the receptor and help activate it, or is it just a passive tail that can be cut off safely?
Cosyntropin, the synthetic ACTH used in a standard adrenal function test, contains only the first 24 of 38 residues. If the remaining segment turns out to contribute meaningfully to receptor activation, it would reopen questions about whether cosyntropin fully mimics the natural hormone in all contexts, and would force a rethink of the minimum fragment needed for a truly equivalent ACTH replacement drug.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.6675508618354797 | boltz-2 |
| ranking score | 0.746398389339447 | 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{pep10670,
sequence = {SYSMEHFRWGKPVGKKRRPVKVYPNGAEDESAQAFPLE},
target = {mc2r},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}