KPV: anti-inflammatory gut peptide (Lys-Pro-Val)
A tiny three-amino-acid fragment of the skin hormone alpha-MSH that calms gut inflammation in animal studies; experimental, not yet an approved drug.
- Class
- Anti-inflammatory tripeptide; alpha-MSH C-terminal fragment
- Status
- Not approved by FDA, EMA, or any major regulatory authority. Not an approved medicine in any major jurisdiction. Under active FDA compounding review (PCAC consultation scheduled July 23, 2026).
- Best-supported effect
- Reduced mucosal inflammation in rodent colitis models (DSS, TNBS, transfer colitis) via direct intracellular NF-κB inhibition; supported by consistent animal-model evidence. In vitro: NF-κB inhibition confirmed across multiple cell types.
- Main caveat
- No published human efficacy trials for any indication; all clinical claims rest on preclinical and mechanistic evidence only.
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.
Snapshot
Class: Anti-inflammatory tripeptide; alpha-MSH C-terminal fragment
Evidence tier: Animal-only evidence
Status: Not approved by FDA, EMA, or any major regulatory authority. Not an approved medicine in any major jurisdiction. Under active FDA compounding review as of April 2026.
Best-supported effect: Reduced mucosal inflammation in rodent colitis models (DSS, TNBS, transfer colitis) via direct intracellular NF-κB inhibition; supported by consistent animal-model evidence
Main caveat: No published human efficacy trials for any indication; all clinical claims rest on preclinical and mechanistic evidence only
What this is
KPV is a tripeptide consisting of three amino acids — lysine, proline, and valine — representing positions 11–13 at the C-terminal end of alpha-melanocyte-stimulating hormone (alpha-MSH). It was identified during systematic dissection of alpha-MSH's activity in the 1980s and 1990s as the minimal sequence retaining substantial anti-inflammatory activity, while lacking the melanocortin receptor-binding sequence responsible for alpha-MSH's pigmentary, appetite, and arousal effects. KPV does not activate MC1R through MC5R and therefore does not produce tanning or other melanocortin-mediated effects. At approximately 342–357 Da (sources differ; see Chemistry), KPV is unusually small for a bioactive peptide and is actively transported across intestinal epithelium via the PepT1 di/tripeptide transporter, providing a mechanistic basis for oral delivery to colonocytes — a property uncommon among peptide drug candidates. Despite several decades of preclinical characterization and a well-characterized mechanism, KPV has not advanced to controlled human clinical trials.
Evidence map
| Evidence layer | Grade | What it supports |
|---|---|---|
| Human | None identified | No human efficacy trials are present. A 2025 systematic review confirms zero human KPV-specific clinical trials identified in the published literature. |
| Animal | Moderate–Strong | Reduced inflammation in DSS-induced colitis, TNBS-induced colitis, and CD45RBhi transfer colitis models; reduced inflammatory markers and histologic damage in rodent studies; skin inflammation reduction in contact dermatitis models; colitis-associated cancer reduction in murine models |
| In vitro | Moderate | NF-κB nuclear translocation inhibition in colonic epithelial cells, macrophages, and keratinocytes; TNF-alpha, IL-6, IL-1beta, and IL-8 reduction; iNOS and nitric oxide suppression; PepT1-mediated uptake confirmed in Caco-2 cells; tight junction protein upregulation; antimicrobial activity against S. aureus (including MRSA) and C. albicans at higher concentrations |
| Computational | Not present | No computational or docking data identified |
| Mechanism | Strong | NF-κB inhibition via IκB-alpha stabilization is well-characterized across multiple cell types. More recent work (Sung et al. 2025, source-cited) extends the mechanism upstream to ERK/p38 MAPK inhibition and caspase-1 blockade. PepT1-mediated intestinal uptake is mechanistically established. Receptor-independence from melanocortin receptors confirmed. |
A large share of the published preclinical evidence traces through a small number of research networks (Merlin/Dalmasso at Emory/Georgia State for gut evidence; Böhm/Brzoska/Luger for skin/immune evidence). Independent replication depth across unaffiliated labs is a consideration for interpreting the evidence base.
Claim check
| Claim | Verdict | Evidence layer | Confidence |
|---|---|---|---|
| Suppresses NF-κB activation and reduces pro-inflammatory cytokines | Supported (in vitro / animal) | In vitro, animal | High — consistent across multiple cell types and colitis models |
| Reduces intestinal mucosal inflammation in colitis models | Supported (animal) | Animal | High — replicated across DSS, TNBS, and transfer colitis models |
| Effective anti-inflammatory treatment for human IBD | Not established | Animal | High — no completed human efficacy trial identified |
| Effective for human skin inflammatory conditions (eczema, psoriasis, dermatitis) | Not established | In vitro, animal | High — preclinical skin models only; no controlled human trial |
| Orally bioavailable via PepT1 transporter | Supported (in vitro / animal) | In vitro, animal | High — PepT1-mediated uptake confirmed in cell and animal models; human pharmacokinetics not characterized |
| Safer than corticosteroids for chronic inflammation | Not established | In vitro, animal (mechanistic) | High — KPV lacks HPA-axis suppression and steroid-class adverse effects per preclinical data; no head-to-head human comparison exists |
| Causes tanning or melanocortin-receptor-mediated effects | Contradicted | In vitro, animal | High — KPV lacks the His-Phe-Arg-Trp MC-receptor-binding sequence; MC1R-knockout experiments confirm receptor-independent mechanism |
Experimental exposure
This section reports exposure used in animal experiments. It does not establish human dosing.
| Context | System | Experimental exposure | Duration | Endpoint | Limitation |
|---|---|---|---|---|---|
| DSS colitis model | Mice (oral administration) | Oral KPV; specific dose not individually extracted from available literature | Days to weeks per model protocol | Disease activity score, colonic inflammation markers, mucosal histology, pro-inflammatory cytokine mRNA | Rodent model; human pharmacokinetics and efficacy not established |
| TNBS colitis model | Mice (oral administration) | Oral KPV; specific dose not individually extracted from available literature | Days to weeks per model protocol | Inflammatory scores, mucosal damage, cytokine levels | Different induction chemistry from DSS; neither model predicts human efficacy |
| CD45RBhi transfer colitis | MC1R-deficient mice | Oral KPV; specific dose not individually extracted | Per model protocol | Survival, colitis severity | MC1R-knockout design confirms non-MCR mechanism; no human translation established |
| Nanoparticle-enhanced delivery | Mice (colitis models) | KPV-loaded hyaluronic acid nanoparticles | Per study protocol | Targeted colonic delivery; inflammation markers | Delivery-system data; no approved formulation exists |
| Contact dermatitis model | Mice (topical application) | Topical KPV; concentration not individually extracted | Per model protocol | Ear swelling, inflammatory infiltrate | Skin model; no human dermatology trial identified |
Preclinical safety signals
| Signal | System | Notes |
|---|---|---|
| No major toxicity at therapeutic doses | Rodent and cell culture models | Source describes no significant toxicity in preclinical studies even at doses above the therapeutic range; duration of studies and full toxicology details not individually extracted |
| Absence of melanocortin-mediated effects | Cell and animal models | KPV does not activate MC1R–MC5R; no pigmentation, appetite, or arousal effects expected or observed |
| Short plasma half-life | per available sources | Short plasma half-life described; stable in GI tract per source; formal PK characterization not available |
| Long-term safety | Not characterized | No chronic animal toxicology data individually extracted; no human safety data in source |
| Pregnancy and reproductive safety | Not characterized | No reproductive toxicology data identified in source |
Regulatory status
| Region / body | Status | Notes |
|---|---|---|
| United States (FDA) | Not approved | Not FDA-approved for any indication. Removed from 503A Category 2 (April 22, 2026) after the nomination was withdrawn. FDA has indicated intent to consult the Pharmacy Compounding Advisory Committee (PCAC) on July 23, 2026 regarding KPV acetate and KPV (free base). Removal from Category 2 does not authorize compounding; KPV remains an unapproved new drug for US compounding purposes until PCAC acts and FDA finalizes. Source: FDA 503A bulk substances document, updated April 22, 2026. |
| European Union | Not approved | No EMA authorization identified in source. per available sources as unapproved investigational peptide. |
| Other major jurisdictions | Not approved | Per available sources, no major regulator (MHRA, TGA, Health Canada) has authorized KPV. |
| WADA | Not listed by name | Per available sources, KPV is not currently listed by name on the WADA Prohibited List. Source also notes that WADA's S0 catch-all category covers substances not approved by any governmental regulatory health authority for human therapeutic use — a description that applies to KPV. per available sources status; current list has not been independently verified in this card. |
Mechanism
KPV's anti-inflammatory mechanism is receptor-independent and intracellular. The peptide crosses cell membranes and enters the cytoplasm, where its primary action is stabilization of the inhibitory IκB-alpha protein that normally sequesters NF-κB in the cytoplasm. By preventing NF-κB nuclear translocation, KPV suppresses transcriptional activation of hundreds of pro-inflammatory genes. Downstream consequences include reduced production of TNF-alpha, IL-6, IL-1beta, IL-8, iNOS, and nitric oxide. More recent work described in the available literature (Sung et al. 2025, Tissue & Cell) extends the mechanism upstream, positioning KPV as a multi-node inhibitor acting on ERK/p38 MAPK signaling and caspase-1 activation in addition to NF-κB. KPV also inhibits inflammasome activation and reduces prostaglandin E2 production per the available literature. This intracellular mechanism is distinct from full-length alpha-MSH, which acts via melanocortin receptors; KPV reaches the same anti-inflammatory downstream state through a receptor-independent intracellular path.
In the gut, PepT1 — a di/tripeptide transporter expressed on intestinal epithelial cells — actively transports KPV intact across the intestinal epithelium. PepT1 expression is upregulated in inflamed intestinal tissue, which may enhance KPV uptake preferentially at inflamed sites. This transport mechanism provides the mechanistic rationale for oral delivery to colonocytes.
Target confidence: The NF-κB/IκB-alpha mechanism is well-established across multiple cell types in available literature literature. The ERK/p38 MAPK and caspase-1 extensions are more recent and not yet as broadly replicated.
Chemistry
| Field | Value |
|---|---|
| Sequence | Lys-Pro-Val |
| Length | 3 amino acids |
| Topology | Linear |
| Molecular formula | C₁₆H₃₁N₅O₄ |
| Molecular weight | 357.4 Da (RP source) / 342.43 g/mol (PE source) — values differ between sources; see note |
| CAS | 67727-97-3 |
| Modifications | None identified; naturally occurring fragment |
| Salt form | KPV (free base) and KPV acetate both mentioned in FDA compounding context |
| Origin | C-terminal fragment (positions 11–13) of alpha-melanocyte-stimulating hormone (alpha-MSH), a 13-amino-acid peptide hormone |
| Sequence confidence | Needs review — sequence itself is consistent across sources; molecular weight values differ between source sections |
Molecular weight note: One available literature reports 342.43 g/mol; another reports 357.4 Da. These values differ by approximately 15 mass units. The discrepancy may reflect different salt forms (free base vs. acetate) or a source error. Both values are preserved here; verification against primary chemistry data is recommended before relying on either value.
Open questions
- Human efficacy translation: No completed controlled human trial has tested whether KPV's substantial animal-model effects translate to clinical benefit in IBD, ulcerative colitis, Crohn's disease, or skin inflammation. This is the most important research gap — the distance between mechanistic strength and clinical validation is large.
- Human pharmacokinetics: PepT1-mediated oral uptake is established in rodent and cell models, but oral bioavailability, distribution, metabolism, and clearance in humans have not been rigorously characterized. Whether KPV reaches the colon at pharmacologically relevant concentrations after oral dosing in humans is unconfirmed.
- Optimal formulation for gut delivery: Preclinical work has investigated nanoparticle and hydrogel delivery systems as superior to standard capsule delivery for colon-targeting. Whether enteric-coated, standard, or targeted-delivery formulations are required for human colonic efficacy is unresolved.
- Long-term safety: No chronic safety data is present in available literature for any species or route. Short plasma half-life and tripeptide structure suggest low accumulation, but long-term immunomodulatory effects are uncharacterized.
- Molecular weight discrepancy: Source sections report 342.43 g/mol and 357.4 Da; verification against a primary chemistry reference is needed.
- US compounding regulatory outcome: FDA has indicated intent to consult PCAC on July 23, 2026 regarding KPV acetate and KPV (free base). The outcome of this process is pending and will be relevant to legal availability of compounded KPV in the US.
- Subcutaneous systemic pharmacodynamics: The mechanistic rationale for KPV is strongest for local routes (oral for gut, topical for skin) where direct tissue contact is the mechanism. Whether subcutaneous injection produces meaningful systemic anti-inflammatory exposure at typical doses has not been established.
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.
Is there a way to treat inflammatory bowel disease that leaves the rest of your immune system working normally?
Most IBD drugs suppress immunity everywhere, raising the risk of serious infections. If this hypothesis holds, KPV would concentrate its anti-inflammatory effect in the intestinal lining and leave circulating immune cells untouched, potentially allowing long-term use without the infection risk that limits current therapies.
Can a small chemical change stop the body from breaking down KPV too quickly before it reaches the gut?
KPV is destroyed rapidly in the digestive tract, which has held back its clinical use. This approach proposes a specific modification that might shield KPV from that degradation while keeping its anti-inflammatory effect intact, which could be a practical step toward a real oral drug.
Does KPV work because a gut protein physically carries it inside cells, or because docking onto that protein already sends a signal?
If the transporter itself triggers the anti-inflammatory signal, that would point to a new target for IBD drugs and help explain why KPV's effect is so localized to the colon. It could open a design path for molecules that work on the surface of gut cells without needing to get inside at all.
Can a gut peptide limit herpes virus activity in mouth and genital tissue by targeting the host cell's own alarm system?
Acyclovir-resistant herpes strains are a real problem for people with weakened immune systems. If KPV blocks the cell-signaling pathway the virus hijacks to replicate, rather than targeting the virus itself, mutations in the virus would not undermine the treatment, which is a meaningful difference for patients who have run out of antiviral options.
Could an anti-inflammatory peptide help stop arteries from calcifying in people with chronic kidney disease?
Calcified arteries are a leading cause of heart attacks and strokes in people with chronic kidney disease, and there is no approved drug to treat it. The standard medications for bone calcification (bisphosphonates) cannot be used safely in kidney patients. If KPV interrupts the inflammatory process that triggers the calcification, it could address a serious unmet need for this population.
Does KPV fight inflammation in two independent ways, or does it only work through a single mechanism?
If KPV blocks the inflammasome (the molecular spark plug for IL-1 beta) separately from its better-known effect on gene expression, it would act like two drugs in one. That combination might explain why it can work at low doses and could make it worth studying for diseases driven primarily by the inflammasome, such as gout and certain rare fever conditions, beyond bowel disease.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.30980703234672546 | openfold3-mlx |
| ranking score | 0.4529377520084381 | openfold3-mlx |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.886 | global PDE — lower = better |
| disorder | 0.122 | fraction disordered |
| chain pair ipTM (A, B) | 0.310 | interface quality |
▸3-letter notation
▸recipeopenfold3-mlx 0.3.1
| parameter | value |
|---|---|
| model | openfold3-mlx 0.3.1 |
| weights | — |
| hardware | — |
| mlx version | — |
| python | — |
| random seed | — |
| msa strategy | — |
| diffusion samples | 1 |
| runtime | 163s |
| predicted by | mlx@peptide |
| predicted at | 2026-05-03 |
▸citationbibtex
@peptide{pep10909,
sequence = {KPV},
target = {mc1r},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}