KPV (lysyl-prolyl-valine)
KPV, Lys-Pro-Val, alpha-MSH(11-13), alpha-MSH C-terminal tripeptide
KPV is the three-amino-acid C-terminal fragment of alpha-melanocyte-stimulating hormone. It retains much of the parent hormone's anti-inflammatory activity without its pigmentary or appetite effects, and has consistent, independently replicated anti-inflammatory data in rodent colitis models. It has never been tested in a human being in any published or registered trial.
Mechanism
KPV is alpha-MSH(11-13), the C-terminal tripeptide of the melanocortin hormone. Its anti-inflammatory activity survives this drastic truncation while the pigmentary and appetite-regulating activities, which require the core melanocortin pharmacophore, do not. Two routes of action have been demonstrated. The first is melanocortin-receptor-dependent signalling: alpha-MSH acts on MC1R expressed by keratinocytes, melanocytes, monocytes and neutrophils to suppress NF-kappaB activation. But Kannengiesser's 2008 work showed KPV rescued MC1R-deficient mice from lethal DSS colitis, which establishes that its activity is at least substantially MC1R-independent.
The second route is more interesting and better characterised. Dalmasso showed in 2008 that KPV is taken up into intestinal epithelial cells by PepT1 (SLC15A1), the di- and tripeptide transporter, and acts intracellularly to inhibit NF-kappaB and MAPK signalling, reducing IL-8 and other cytokine output. This mechanism has a built-in elegance: PepT1 is minimally expressed in healthy colon but is strongly upregulated in inflamed colonic epithelium, so the peptide is preferentially imported precisely where inflammation is occurring. KPV also has direct antimicrobial activity against Staphylococcus aureus and Candida albicans, an activity shared with the parent hormone and independent of host receptors.
What the research shows
The preclinical evidence is unusually good for this class because it has been reproduced by unrelated groups. Kannengiesser demonstrated benefit in two mechanistically distinct colitis models, chemical DSS injury and CD45RB-high T-cell transfer colitis, with reduced myeloperoxidase activity, reduced histological inflammation and faster weight regain. Dalmasso established the PepT1 transport mechanism in Gastroenterology. Getting had earlier dissected which parts of alpha-MSH carry the anti-inflammatory effect, and Land showed suppression of TNF-alpha- and respiratory syncytial virus-evoked NF-kappaB signalling in immortalised human bronchial epithelial cells, also implicating an MC3R-agonist component. This is a coherent, replicated body of work.
What happened next is the most informative thing in the file. Nearly all subsequent research has been drug-delivery engineering rather than efficacy testing: hyaluronic-acid-functionalised nanoparticles for oral colonic delivery, cysteamine-grafted polyglutamic acid hydrogels, self-assembled carrier-free nanodrugs, and inflammation-triggered self-immolative oral conjugates. Investigators keep building increasingly elaborate vehicles for KPV, which is a strong signal that the free peptide does not survive administration well enough to work as a plain systemic or oral drug. Despite eighteen years since the mechanism was established, a query of the ClinicalTrials.gov v2 API for KPV as an intervention returns no records, and PubMed contains no human study. It is nonetheless marketed heavily online for gut health, skin conditions, mast cell disorders and general healing. None of those uses has any human support whatsoever.
Evidence assessment
Preclinical only
Well-replicated cell and rodent data across multiple independent laboratories, but a ClinicalTrials.gov query returns no registered trial with KPV as an intervention, and PubMed contains no human efficacy or safety study of any kind.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation Preclinical only
KPV enters epithelial cells via the PepT1 di/tripeptide transporter and inhibits NF-kappaB and MAPK signalling, reducing cytokine output and colonic inflammation.
Melanocortin-derived tripeptide KPV has anti-inflammatory potential in murine models of inflammatory bowel disease Preclinical only
KPV reduced inflammatory infiltrate, myeloperoxidase activity and weight loss in both models, and rescued MC1R-deficient mice from death during DSS colitis, indicating MC1R-independent activity.
Dissection of the anti-inflammatory effect of the core and C-terminal (KPV) alpha-melanocyte-stimulating hormone peptides Preclinical only
Separates which alpha-MSH regions carry anti-inflammatory activity, establishing that the C-terminal KPV tripeptide retains much of the parent effect.
Orally Targeted Delivery of Tripeptide KPV via Hyaluronic Acid-Functionalized Nanoparticles Efficiently Alleviates Ulcerative Colitis Preclinical only
Targeted nanoparticle delivery substantially improved KPV's effect on colitis relative to free peptide.
Inhibition of cellular and systemic inflammation cues in human bronchial epithelial cells by melanocortin-related peptides: mechanism of KPV action and a role for MC3R agonists Preclinical only
KPV and gamma-MSH suppressed NF-kappaB-driven inflammatory signalling in human airway epithelium, extending the mechanism beyond gut tissue and implicating an MC3R-agonist component.
Safety
No human safety data exist. There is a weak indirect reassurance, in that the parent hormone alpha-MSH has been studied for decades and the tripeptide lacks the melanocortin pigmentary and cardiovascular effects that complicate full melanocortin agonists. But that is an inference from structure, not evidence from exposure. Nothing is known about immunogenicity, repeat dosing, or interaction with the gut microbiome given the peptide's antimicrobial activity. The practical hazard for anyone obtaining it is unregulated manufacture: purity, sterility, endotoxin content and even sequence identity are unverified in research-grade material.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | No MHRA authorisation. Not an authorised medicine, licensed supplement or permitted cosmetic active with therapeutic claims. Supplied for human use it would meet the definition of a medicinal product under the Human Medicines Regulations 2012. |
| United States | Not FDA-approved for any indication and never entered clinical development. KPV was among the peptides placed on the FDA's interim 503A Category 2 compounding list in September 2023; that list was later revised following nomination withdrawals and peptide nominations were referred to the Pharmacy Compounding Advisory Committee. Sold online labelled 'for research use only'. |
| WADA (sport) | Not individually named on the Prohibited List. Athletes using any unapproved peptide should note that S0 captures substances with no current regulatory approval for human therapeutic use, and should seek guidance from their anti-doping organisation. |
Questions
None. A query of the ClinicalTrials.gov registry returns no trial with KPV as an intervention for any indication, and PubMed contains no published human study. The mechanism was established in 2008 and the compound has still never been given to a person in a documented trial. Everything known about it comes from cell culture and rodents.
Because of genuinely good mouse data. KPV reduces inflammation in two different colitis models and enters inflamed gut epithelium through the PepT1 transporter, which is upregulated in inflammation. That is a real and elegant mechanism. It is also entirely preclinical, and mouse colitis models have a poor record of predicting what works in human inflammatory bowel disease.
No. KPV is the last three amino acids of alpha-MSH, positions 11 to 13. It keeps much of the anti-inflammatory activity while losing the pigmentary, appetite-suppressing and other melanocortin receptor effects that require the intact core of the hormone. That selectivity is the point of using the fragment.
Yes, this is documented in the preclinical literature: both alpha-MSH and the KPV fragment show direct activity against Staphylococcus aureus and Candida albicans. What that means for a person taking it is unknown, including whether it would perturb the gut microbiome, which has never been studied.