PHM-27: natural nerve signaling peptide made alongside VIP
A natural body-made peptide produced in nerve cells alongside VIP, a related signaling molecule; studied as a research tool, not an approved drug.
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.
Endogenous peptide — produced naturally and routinely synthesized for research
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Endogenous peptide — receptor binding and activity established in published literature
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What this is
PHM-27 (Peptide Histidine Methionine-27) is a 27-amino-acid neuropeptide found naturally in humans. It is co-produced with the better-known vasoactive intestinal peptide (VIP) — both are cut from the same precursor protein in nerve cells and certain secretory tissues. PHM-27 is the human counterpart of porcine PHI-27 (Peptide Histidine Isoleucine-27), a peptide isolated from pig intestine; the "M" vs "I" in the names reflects that the human version ends in methionine where the porcine version ends in isoleucine. The stored 27-residue sequence carries a C-terminal amide group (-NH₂) that is not visible in the raw one-letter code — this modification is characteristic of the mature, biologically active form.
History
PHM-27 was identified in 1983 when Itoh and colleagues cloned the cDNA encoding human prepro-VIP and found that the same precursor encodes a second peptide with structural similarity to porcine PHI-27. They named it PHM-27 to reflect its human origin and C-terminal methionine (Itoh and colleagues, Nature 1983). The discovery established that VIP and PHM-27 are co-expressed from a single gene — prepro-VIP/PHM-27 — with PHM-27 occupying residues 81–107 and VIP occupying residues 125–152 of the precursor protein. This shared-precursor arrangement placed both peptides within the glucagon-secretin family of structurally related hormones and neuropeptides.
What it does
PHM-27 acts as an agonist at the VPAC1 receptor, one of the two main VIP receptor subtypes, triggering production of the intracellular messenger cAMP. In this way it shares functional overlap with VIP, though the two peptides are not identical in their receptor pharmacology. In the pancreas, in vivo studies in transgenic mice showed that expression of the VIP/PHM-27 gene in beta cells was associated with improved glucose tolerance and enhanced insulin secretion attributable to both VIP and PHM-27 (Kato and colleagues, J. Biol. Chem. 1994, cited in Kato and colleagues; also referenced in Sandoval and colleagues, Front. Endocrinol. 2022).
Evidence
- Human: No human clinical trials specifically studying PHM-27 have been published. PHM-27's characterization derives from molecular biology and preclinical work.
- Animal: Transgenic mice overexpressing the VIP/PHM-27 gene in pancreatic beta cells demonstrated improved glucose tolerance and enhanced insulin secretion, with both VIP and PHM-27 implicated as active agents (Kato and colleagues, 1994, cited in Sandoval and colleagues, Front. Endocrinol. 2022).
- In vitro: PHM-27 stimulates cAMP production through VPAC1 receptor activation in cell-based assays (Ishihara and colleagues, Yakugaku Zasshi 2002).
Mechanism
PHM-27 is a member of the glucagon-secretin superfamily and signals through G-protein-coupled receptors. It binds the VPAC1 receptor (also designated VPAC₁ or VIPR1), a Gₛ-coupled receptor, stimulating adenylyl cyclase and raising intracellular cAMP levels. This signalling profile parallels that of VIP, its co-encoded sister peptide. PHM-27 is structurally homologous to porcine PHI-27; the N-terminal histidine is conserved across both peptides and is characteristic of the PHI/PHM subfamily within the broader VIP/PACAP/glucagon peptide family.
Related peptides
- VIP (vasoactive intestinal peptide) — co-encoded with PHM-27 in the same prepro-VIP/PHM-27 precursor; the primary ligand at VPAC1 and VPAC2 receptors.
- PACAP — related neuropeptide in the same glucagon-secretin family; potent activator of PAC1, VPAC1, and VPAC2 receptors.
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 PHM-27 grip the VIP receptor at the same places VIP does, or does its different tail change where it lands?
If PHM-27 touches the receptor differently, it could be engineered into a drug that selectively triggers some VIP receptor effects but not others, potentially avoiding side effects linked to full VIP-like activation.
Could a small chemical swap at the end of PHM-27 prevent it from breaking down in oxidizing environments, like inflamed tissue, without weakening its activity?
If this single substitution works, it would convert a fragile natural peptide into a stable therapeutic candidate suitable for inhaled or injectable treatment of inflammatory diseases, at minimal engineering cost.
Is PHM-27 silently protecting the airways alongside VIP, and could its loss contribute to asthma attacks?
If PHM-27 independently helps keep airways open and calm, its absence in asthmatic patients could explain why some people respond poorly to current treatments, and measuring it could help doctors identify who needs a new type of neuropeptide-based inhaler.
Does PHM-27 activate only one of the two VIP receptors while leaving the other mostly untouched?
If PHM-27 naturally favors one receptor, it could be turned into a more precise anti-inflammatory drug than VIP-based treatments, hitting the right target in diseases like Crohn's disease or asthma without off-target effects from the second receptor.
When both peptides arrive at the same receptor at the same time, do they together push the cell harder than the sum of their individual effects?
If this cooperative effect is real, it could explain why certain nerve-driven responses, such as airway relaxation or gut secretion, are stronger than VIP levels alone would predict, and it would suggest that mimicking the pair rather than VIP alone would make better drugs.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.8466119170188904 | openfold3-mlx |
| ranking score | 0.9126150012016296 | openfold3-mlx |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.817 | global PDE — lower = better |
| disorder | 0.190 | fraction disordered |
| chain pair ipTM (A, B) | 0.847 | 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 | 403s |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
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{pep04465,
sequence = {HADGVFTSDFSKLLGQLSAKKYLESLM},
target = {vpac1},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}