KPV (Lys-Pro-Val)
KPV is a synthetic C-terminal tripeptide fragment (Lys-Pro-Val) derived from alpha-melanocyte-stimulating hormone (α-MSH, residues 11–13). At nanomolar concentrations, KPV inhibits NF-κB and MAP kinase inflammatory signalling in intestinal epithelial cells without requiring melanocortin receptor engagement, making it one of the most potent small anti-inflammatory peptides characterized in experimental colitis models. Preclinical efficacy in DSS and TNBS colitis is well-replicated; oral bioavailability is poor for the free peptide but nanoparticle encapsulation dramatically improves mucosal delivery. No human clinical trials have been registered or completed as of 2026-05-09. KPV had become popular among functional-medicine practitioners for gut inflammation before regulatory review of compounded peptides (FDA 503A/503B actions, 2024).
Identity
| Property | Value |
|---|---|
| Sequence | H-Lys-Pro-Val-OH |
| Derivation | α-MSH residues 11–13 (C-terminus) |
| PubChem CID | 125672 |
| ChEMBL ID | null — not confirmed; gap noted below |
| Molecular formula | C16H30N4O4 |
| Molecular weight | 342.43 Da |
| Stereochemistry | All-L amino acids (natural configuration) |
| PepT1 substrate | Yes — transported into intestinal epithelial cells via the oligopeptide transporter SLC15A1/PepT1 1 |
needs-canonical-id — ChEMBL ID could not be confirmed via API lookup (short peptide search returned a structurally unrelated compound). Recommend manual search at ebi.ac.uk/chembl using InChI.
Mechanism of action
NF-κB and MAPK inhibition (primary, receptor-independent)
KPV inhibits NF-κB activation indirectly — by delaying IκBα degradation and accelerating IκBα recovery to baseline — and suppresses MAP kinase phosphorylation of ERK1/2, JNK, and p38 in intestinal epithelial cells at nanomolar concentrations (10 nmol/L in vitro) 1. These effects reduce IL-8 mRNA and protein in vitro; in vivo cytokine reduction (IL-6, IL-12, IFN-γ, IL-1β) is documented in the DSS model. Critically, the anti-inflammatory activity of KPV in colitis mouse models persists in MC1R-deficient animals, demonstrating that it is at least partially independent of melanocortin-1 receptor signalling 2. This distinguishes KPV from full-length α-MSH, which acts predominantly via MC1R/MC3R cAMP-PKA pathways.
Note: KPV does not raise intracellular cAMP in IECs (confirmed by ELISA in Dalmasso 2008), and α-MSH at equivalent concentrations does not replicate KPV’s IκBα kinetics, consistent with non-MCR-mediated action in IECs.
The molecular mechanism beyond IκBα preservation is not fully resolved. KPV does not appear to act as a classical competitive receptor antagonist; the receptor through which it acts in IEC-6 and Caco-2 cells remains unconfirmed. no-mechanism
PepT1-mediated intestinal uptake
Uptake of KPV into intestinal epithelial cells occurs via the H+/oligopeptide co-transporter PepT1 (SLC15A1), which is overexpressed in inflamed colonic epithelium 1. This uptake mechanism provides both a route for intracellular delivery and a rationale for targeting nanoparticle delivery systems: PepT1 overexpression in inflamed tissue creates selective enrichment of KPV in the pathological zone. Anti-inflammatory effects require intracellular KPV based on the PepT1-dependence observed in Dalmasso 2008.
Anti-inflammatory cytokine profile
In preclinical colitis models, KPV treatment reduces 1 2:
- IL-6, IL-12, IFN-γ, IL-1β mRNA in DSS-colitis colon (Dalmasso 2008); TNF-α, IL-1β, IL-6, IFN-γ mRNA in TNBS-colitis colon (Dalmasso 2008)
- Myeloperoxidase (MPO) activity — a marker of neutrophil infiltration (~50% reduction in DSS model, Dalmasso 2008)
- Mucosal inflammatory-cell infiltrate by histology
This is consistent with the broader α-MSH anti-inflammatory programme characterised by Luger, Brzoska, and co-workers, who showed that α-MSH-derived peptides inhibit NF-κB, reduce adhesion molecule expression, and suppress Th1/Th17-type immune polarisation without producing global immunosuppression in animal models 3.
Antimicrobial activity (secondary)
Catania et al. (2000) showed that α-MSH and its C-terminal fragment KPV exhibited inhibitory activity against Staphylococcus aureus and Candida albicans in an in vitro host-defence study 4. The “without suppressing the immune system” characterisation in the literature refers to the anti-inflammatory (not immunosuppressive) phenotype of the peptide — KPV reduces excessive inflammatory signalling but does not ablate innate immune killing capacity. The antimicrobial data are limited to a single report; mechanism (membrane disruption vs receptor-mediated) is not defined. needs-replication
Note: antimicrobial activity is not catalogued as a mechanism class value in mechanisms: frontmatter — no antimicrobial-peptide class currently exists in intervention-classes. Activity is documented here in body prose. See return summary for escalation.
Preclinical colitis efficacy
| Study | Model | Route | Dose/schedule | n/group | Key outcomes |
|---|---|---|---|---|---|
| Dalmasso 2008 1 | DSS (3% in drinking water, 8 days) + TNBS (150 mg/kg intracolonic, assessed 48 h) colitis; female C57BL/6 mice | Oral (drinking water) | 100 µmol/L KPV in drinking water | 10 | Reduced body weight loss, MPO activity (~50% reduction), colonic shortening, and pro-inflammatory cytokine mRNA (IL-6, IL-12, IFN-γ, IL-1β in DSS; TNF-α, IL-1β, IL-6, IFN-γ in TNBS); NF-κB and MAPK (ERK1/2, JNK, p38) inhibition in Caco-2-BBE cells at 10 nmol/L |
| Kannengiesser 2008 2 | DSS colitis + CD45RB^hi transfer colitis (mouse); also MC1Re/e (nonfunctional MC1R) mice in DSS model | Not specified in abstract | Not specified in abstract | Not specified in abstract | Earlier recovery and body weight regain; reduced inflammatory infiltrates and MPO activity; KPV rescued all MC1Re/e mice from death in DSS colitis, confirming MC1R-independent mechanism |
| Laroui 2010 5 | DSS (3%) colitis (mouse, C57BL/6); 7-day daily oral gavage | Oral gavage (150 µL hydrogel/day) | NP-KPV: ~25.2 ng/day delivered to colon; equivalent free KPV effective dose ~200 µg/day (12,000-fold difference) | 8 (MPO/cytokine groups); 12 (FITC localization) | Reduced MPO activity and TNF-α/IL-1β mRNA; histologic colitis improvement; free KPV at equivalent concentration (41 µg/L) had no effect on MPO |
All data are preclinical mouse or rat models. No completed human clinical trials as of 2026-05-09. needs-human-replication
| Dimension | Status |
|---|---|
| Pathway conserved in humans? | Yes — NF-κB and MAPK are canonical human inflammatory pathways; PepT1 is expressed in human intestinal epithelium |
| Phenotype (anti-inflammatory colitis effect) conserved in humans? | Unknown — not tested in vivo in humans |
| Replicated in humans? | No — no completed human trial |
Oral nanoparticle delivery
Free KPV peptide is subject to rapid intestinal proteolysis and poor mucosal penetration at oral doses. Laroui et al. (2010) demonstrated that encapsulation in alginate-chitosan-coated PLA (polylactic acid) nanoparticles (~366 nm diameter by PCS) targeted to the colon achieved equivalent colitis efficacy at doses 12,000-fold lower than free peptide oral administration in DSS-colitis mice 5. The effective free KPV dose in drinking water was ~200 µg/day; the NP formulation delivered ~25.2 ng/day to the colonic lumen via daily gavage. Subsequent groups have developed hydrogel systems (TNBS-rat models, PMIDs 35245681, 34547895) and liposomal formulations for topical mucosal delivery. These delivery-platform studies consistently show:
- Colonic accumulation is enhanced by PepT1 overexpression in inflamed tissue
- KPV retains anti-inflammatory bioactivity after encapsulation
- Local mucosal barrier repair (epithelial junction proteins, mucin production) is improved alongside cytokine suppression
The Merlin/Sitaraman group (Emory University) pioneered the nanoparticle delivery platform and is the dominant group in this literature 1 5.
Functional-medicine use and regulatory status
KPV was widely used by compounding pharmacies in the USA (typically 500 µg–2 mg capsules, sometimes as peptide injections) for off-label treatment of gut inflammation and IBD-related symptoms in the 2018–2024 period. This use preceded any clinical trial establishing efficacy or safety in humans.
Regulatory context: In 2023–2024, the FDA’s Pharmacy Compounding Advisory Committee (PCAC) reviewed a list of peptides under the 503A/503B category. KPV, along with many other research peptides (BPC-157, TB-500, etc.), was placed on the FDA’s list of bulk substances that may not be used in compounding under 503A, effectively prohibiting most compounding-pharmacy access in the USA as of 2024. The regulatory basis was absence of clinical evidence, not demonstrated harm. Status in other jurisdictions varies. needs-replication
Aging relevance
KPV does not have a direct entry in GenAge or DrugAge as of 2026-05-09 (no lifespan-extension data in any model organism). Its aging relevance is indirect:
- Inflammaging: chronic-inflammation is a core driver of most aging hallmarks via cytokine-mediated tissue damage (see chronic-inflammation). KPV’s potent NF-κB/MAPK inhibition at nanomolar concentrations positions it as a mechanistically interesting anti-inflammaging agent if oral bioavailability can be resolved.
- Intestinal barrier aging: Gut barrier function and mucosal immunity decline with age, contributing to low-grade endotoxemia and systemic inflammation. KPV’s demonstrated mucosal healing and barrier-restoration effects in colitis models may have relevance to gut-aging processes, but this is speculative. unsourced
Knowledge gaps and limitations
| Gap | Tag | Status |
|---|---|---|
| No human clinical trial | needs-human-replication | 0 active ClinicalTrials.gov registrations as of 2026-05-09 |
| KPV molecular receptor unknown | no-mechanism | MC1R independence confirmed; target receptor not identified |
| Dose-response in humans unknown | dose-response-unclear | All dosing from preclinical models; allometric scaling not validated |
| Antimicrobial mechanism undefined | needs-replication | Single in vitro study; no in vivo antimicrobial trial |
| ChEMBL ID unconfirmed | needs-canonical-id | Automated lookup failed; manual cross-check recommended |
| Long-term safety | long-term-unknown | No chronic-exposure study in any species |
| Aging-specific effects | needs-replication | No GenAge/DrugAge entry; no aged-animal colitis model using KPV |
Footnotes
Footnotes
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doi:10.1053/j.gastro.2007.10.026 · Dalmasso G, Charrier-Hisamuddin L, Nguyen HTT, Yan Y, Sitaraman S, Merlin D · Gastroenterology 2008;134(1):166-178 · in-vitro (Caco-2-BBE, HT29-Cl.19A, Jurkat) + in-vivo (female C57BL/6 DSS 3% + TNBS 150 mg/kg colitis) · n=10/group (in vivo) · dose: 100 µmol/L KPV in drinking water (in vivo); 10 nmol/L (in vitro) · KPV at 10 nmol/L delays IκBα degradation and suppresses ERK1/2, JNK, and p38 phosphorylation; PepT1 (Km ~160 µmol/L) mediates uptake and is required for anti-inflammatory effect; oral KPV reduces DSS- and TNBS-induced colitis severity, MPO activity, and pro-inflammatory cytokine mRNA · cited 120 times (archive confirmed; PDF verified) ↩ ↩2 ↩3 ↩4 ↩5 ↩6
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doi:10.1002/ibd.20334 · PMID:18092346 · Kannengiesser K, Maaser C, Heidemann J, Luegering A, Ross M, Brzoska T, Bohm M, Luger TA, Domschke W, Kucharzik T · Inflammatory Bowel Diseases 2008;14(3):324-331 · in-vivo (DSS colitis + CD45RB^hi transfer colitis, mouse; also MC1Re/e nonfunctional-MC1R mice in DSS model) · effects persist in MC1Re/e mice, confirming MC1R-independent mechanism; KPV rescued all MC1Re/e animals from death in DSS colitis · reduced inflammatory infiltrate + MPO activity; earlier body weight recovery · cited 53 times · no-fulltext-access — closed-access; verified against PubMed abstract (PMID:18092346) only ↩ ↩2 ↩3
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doi:10.1136/ard.2007.079780 · Luger TA, Brzoska T · Ann Rheum Dis 2007;66 Suppl 3:iii52-55 · review · α-MSH-derived peptides as anti-inflammatory / immunomodulating class; NF-κB suppression, adhesion molecule reduction, cytokine modulation; anti-inflammatory without global immunosuppression in animal models · cited 58 times · not independently PDF-verified in this pass ↩
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doi:10.1111/j.1749-6632.2000.tb05387.x · PMID:11268348 · Catania A, Cutuli M, Garofalo L, Carlin A, Airaghi L, Barcellini W, Lipton JM · Ann N Y Acad Sci 2000;917:227-231 · in-vitro antimicrobial assay (conference proceedings) · α-MSH and its C-terminal fragment KPV showed inhibitory influences against Staphylococcus aureus and Candida albicans; also reduces NF-κB activation and HIV replication in monocytes · cited 41 times · no-fulltext-access — not_oa; verified against PubMed abstract (PMID:11268348) only. Note: more detailed antimicrobial mechanism data (cAMP elevation in pathogens; no reduction of neutrophil killing capacity) is in the companion paper Cutuli M et al. 2000 (J Leukoc Biol 67:233-239, PMID:10670585) ↩
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doi:10.1053/j.gastro.2009.11.003 · Laroui H, Dalmasso G, Nguyen HTT, Yan Y, Sitaraman SV, Merlin D · Gastroenterology 2010;138(3):843-853 · in-vivo (DSS colitis, C57BL/6 mouse; 7-day daily oral gavage 150 µL hydrogel) · n=8 (MPO/cytokine); n=12 (FITC localization) · PLA (~366 nm) nanoparticles encapsulated in alginate-chitosan hydrogel (7/3 wt/wt); effective colonic dose via NP ~25.2 ng/day vs ~200 µg/day free KPV in drinking water — 12,000-fold dose reduction confirmed; free KPV at equivalent concentration (41 µg/L) had no effect on MPO or cytokines · cited 241 times (archive confirmed; PDF verified) ↩ ↩2 ↩3