Stress-response research peptide (oxidized CRF 1-40)
A lab-only synthetic peptide, based on a pig version of a human stress hormone, that switches on a receptor (CRHR2) linked to calming anxiety and protecting the heart during stress recovery.
- Class
- Corticotropin-releasing factor (CRF) variant — porcine hypothalamic peptide
- Status
- No approved therapeutic status identified. Catalog and database entry context only.
- Best-supported effect
- Isolated from porcine hypothalami and characterized as having corticotropin-releasing factor activity in a single 1986 purification study (Patthy et al.); no independent assay, animal-model, or clinical evidence is attached to this card.
- Main caveat
- This card is based on a single catalog/database source with one primary reference. No receptor-binding, efficacy, safety, animal-model, 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
Corticotropin-releasing factor [1–40; M38-oxidized, N40] is a 40-residue synthetic analog of porcine corticotropin-releasing factor (CRF), differing from the native sequence at position 38 where methionine has been chemically oxidized to methionine sulfoxide. The peptide was originally characterized as one of several CRF-related polypeptides isolated from porcine hypothalami by Patthy and colleagues (Patthy et al., PNAS 1986); the synthetic oxidized form is used as a research tool for probing CRF receptor pharmacology, with particular selectivity for the type-2 CRF receptor (CRHR2). The oxidized methionine at position 38 is not visible in the stored 40-letter sequence — it is a post-synthetic chemical modification that materially affects receptor subtype selectivity.
History
The sequence of porcine CRF [1–40] was established through biochemical isolation work: Patthy and colleagues (PNAS 1986) purified a series of CRF-active polypeptides from porcine hypothalami using gel filtration and reversed-phase HPLC, and confirmed their structures by sequence analysis. The isolated peptides were characterized by their ability to stimulate corticotropin (ACTH) release from superfused rat pituitary cells. The oxidized M38 variant documented here — bearing methionine sulfoxide at residue 38 and asparagine at the C-terminal position 40 — emerged from this characterization work as a structurally defined form suitable for receptor binding studies.
What it does
In biological systems, CRF [1–40] analogs act on the HPA (hypothalamic–pituitary–adrenal) axis by stimulating ACTH release from the anterior pituitary, which in turn drives cortisol production by the adrenal cortex. The [1–40; M38-oxidized, N40] variant is primarily a laboratory research reagent rather than a therapeutic agent: its value lies in its defined receptor subtype profile. By binding CRHR2 — a class B G protein-coupled receptor expressed in peripheral tissues including the heart, skeletal muscle, and gastrointestinal tract — this analog is used to investigate CRHR2-mediated roles in stress recovery, anxiolysis, and cardioprotective signaling, pathways that are distinct from the classical HPA-axis stress response mediated primarily through CRHR1.
Evidence
- Human: No clinical trials reported for this specific analog.
- Animal: CRF [1–40] peptides from porcine hypothalami were shown to stimulate corticotropin release from rat pituitary cells in the original isolation work (Patthy et al., PNAS 1986). Broader preclinical literature on CRHR2-selective ligands in animal models exists within the CRF receptor pharmacology field.
- In vitro: Receptor binding characterization consistent with CRHR2 selectivity has been the primary application of this oxidized variant in research settings.
Mechanism
The native CRF [1–40] peptide activates both CRHR1 and CRHR2, which are class B GPCRs that signal primarily through Gs-coupled cAMP elevation. The M38-oxidized variant alters the local structure of the C-terminal helix region of CRF, where Met38 is part of a conserved hydrophobic surface involved in receptor engagement. This modification shifts the receptor subtype selectivity profile toward CRHR2, making the [M38-oxidized, N40] form a useful probe for dissecting CRHR2-specific signaling from the CRHR1-dominated HPA-axis responses. CRHR2 is expressed peripherally — in the cardiovascular system, gut, and skeletal muscle — where it mediates stress recovery and anxiolytic responses rather than ACTH secretion.
Related peptides
The CRF/urocortin family includes several peptides with overlapping but distinct receptor pharmacology. Native porcine CRF [1–40] (the unoxidized parent sequence) was characterized in the same isolation work (Patthy et al., PNAS 1986). Urocortin peptides (urocortin I, II, and III) are endogenous mammalian ligands with preferential CRHR2 selectivity. ACTH (adrenocorticotropic hormone), the downstream pituitary hormone that CRF drives, is covered on its own platform card.
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 the oxidized amino acid near the end of this peptide explain why it binds one stress receptor but not the other?
If confirmed, this insight could guide the design of drugs that activate the body's stress-recovery system without triggering the acute anxiety-driving receptor, potentially helping people with stress-related disorders.
Does the oxidized form of this stress hormone keep its receptor active longer than the normal version by avoiding the cell's usual receptor-switching-off mechanism?
If so, this oxidized peptide could be a template for longer-acting drugs that support recovery after stress, with potential uses in anxiety disorders, heart failure, and metabolic conditions.
Does the oxidized form of this peptide attach to the CRHR2 receptor in a different physical orientation than the normal version?
Understanding this could allow chemists to engineer stress-hormone drugs with a built-in chemical modification that makes them more stable in the body while still selectively calming the stress response.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.8020362854003906 | openfold3-mlx |
| ranking score | 0.8720787167549133 | openfold3-mlx |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.709 | global PDE — lower = better |
| disorder | 0.171 | fraction disordered |
| chain pair ipTM (A, B) | 0.802 | interface quality |
▸3-letter notation
▸recipeopenfold3-mlx 0.3.1
| parameter | value |
|---|---|
| model | openfold3-mlx 0.3.1 |
| weights | aedd8f3eb814e392… |
| hardware | apple_m4_base_16gb |
| mlx version | 0.31.1 |
| python | 3.14.3 |
| random seed | 42 |
| msa strategy | colabfold |
| diffusion samples | 1 |
| runtime | 350s |
| predicted by | mlx@peptide |
| predicted at | 2026-04-22 |
python3 openfold3/run_openfold.py predict --query_json {query.json} --runner_yaml examples/example_runner_yamls/mlx_runner.yml --output_dir {output_dir} --num_diffusion_samples 1 ▸citationbibtex
@peptide{pep10651,
sequence = {SEEPPISLDLTFHLLREVLEMARAEQLAQQAHSNRKLMEN},
target = {crhr2},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}