Research Dossier on KPV

(Anti-inflammatory Peptide)

Classification & Molecular Identity

Amino-acid sequence, molecular weight, structural motifs

• Common name: KPV

• Systematic identity: L-lysyl-L-prolyl-L-valine (C-terminal tripeptide of α-melanocyte-stimulating hormone, α-MSH)

• Sequence (one-letter): Lys–Pro–Val (K–P–V)

• Approximate relative molecular mass (free peptide): ≈ 342.45 g·mol⁻¹ (tri-residue mass + H₂O)

• Key motifs:

  • Proline confers conformational constraint.

  • Hydrophobic Val at the C-terminus supports membrane interaction/transport.

  • C-terminal amidation is sometimes used in experimental analogs but is not inherent to the native α-MSH11–13 motif.

• Origin within α-MSH: KPV corresponds to residues 11–13 of α-MSH (sequence of human α-MSH includes “…GKPV-NH₂” at the C-terminus). Both α-MSH and Ac-KPV derivatives are discussed in medicinal-chemistry studies. PMC

Discovery history (lab, year, species)

KPV emerged from efforts to minimize α-MSH while retaining anti-inflammatory actions. By the late 1990s–early 2000s, pharmacology groups showed that much of α-MSH’s anti-inflammatory activity localizes to its C-terminal tripeptide KPV, leading to extensive evaluation of KPV in keratinocyte, colitis, and barrier-epithelium models. PMC

Endogenous vs synthetic origin

• Endogenous context: KPV is the C-terminal fragment within the endogenous neuropeptide α-MSH (a cleavage product of proopiomelanocortin, POMC).

• Research material: Experimental KPV used in studies is synthetic (solid-phase peptide synthesis), sometimes acetylated or amidated experimentally to probe stability or receptor interactions. PMC

Homologs, analogs, derivatives

• KdPT (Lys-D-Pro-Thr) and KP-D-V are α-MSH-derived tripeptide analogs designed to retain or enhance anti-inflammatory signaling while altering pigmentary activity or pharmacokinetics. PMC+1

• PepT1-targeted prodrug/nano-formulations of KPV have been engineered to increase local mucosal exposure in colitis models and dramatically reduce the effective dose. Gastro Journal+1

Historical Development & Research Trajectory

Key milestones in discovery and study

1. α-MSH miniaturization (1990s–2007): Pharmacology work showed that KPV can reproduce α-MSH’s anti-inflammatory actions in several models, motivating the concept that the C-terminal 11–13 segment is a core effector. PMC

2. Proof-of-concept in murine colitis (2008): Two independent studies demonstrated that KPV reduces disease activity in dextran sulfate sodium (DSS) colitis and T-cell transfer colitis. Strikingly, benefit persisted in MC1R-deficient (MC1R^e/e) mice, suggesting at least partial independence from canonical melanocortin receptor (MC1R) signaling. (Investigational murine doses used in study Kannengiesser 2008.) PubMed+1

3. Transporter biology (2008): Dalmasso et al. established that PepT1 (the intestinal di/tri-peptide transporter) mediates KPV uptake into intestinal epithelial and immune cells, and that KPV’s anti-inflammatory activity depends on PepT1. (Investigational doses used in study Dalmasso 2008.) PubMed+1

4. Targeted delivery & dose-sparing (2009–2012): Laroui et al. developed colon-targeted hydrogel nanoparticlescarrying anti-inflammatory agents (including KPV-loaded systems) that increased local drug exposure and reduced required doses by several orders of magnitude in rodent colitis. (Investigational nano-doses used in Laroui 2010/2012.) PubMed+2Gastro Journal+2

5. PepT1 in colitis-associated cancer (2016): Viennois et al. showed that PepT1 expression promotes colitis-associated tumorigenesis (CAC) and that KPV prevents CAC in wild-type mice but not in PepT1-knockout mice, underscoring the transporter-dependence of both uptake and therapeutic effect. (Investigational regimens used in Viennois 2016.) PMC+1

Paradigm shifts and controversies

• From melanocortin receptor to transporter-enabled action. Early assumptions that KPV strictly signaled through MC1R were revised: anti-inflammatory effects persisted in MC1R-deficient mice, redirecting attention to PepT1-facilitated entry and MC1R-independent pathways in epithelia and immune cells. PubMed

• Barrier-first pharmacology. The discovery that PepT1 is up-regulated in inflamed intestinal mucosa reframed KPV as a disease-targeted cargo—a peptide whose absorption is enhanced at sites of inflammation, potentially improving local selectivity. PubMed

• Translational gap. Despite strong preclinical signals, well-powered human trials are not yet available; reported clinical-grade data for KPV alone are limited, and no completed Phase II/III RCTs dedicated to KPV were identified as of September 26, 2025. (Not established.) PMC

Evolution of scientific interest

Interest has progressed from dermatology/keratinocyte anti-inflammation to mucosal immunology, barrier transport, and colitis-associated oncogenesis (CAC). The modern literature emphasizes PepT1 biology, nanocarrier strategies, and receptor-independent anti-inflammatory mechanisms, while acknowledging the gap in human efficacy datasets. PMC+1

Mechanisms of Action

Primary and secondary receptor interactions

• MC1R and melanocortin family context. α-MSH exerts anti-inflammatory effects via melanocortin receptors (notably MC1R). However, KPV’s protection in MC1R-deficient mice implies that KPV can act independentlyof MC1R in relevant contexts (e.g., inflamed colon). PubMed

• PepT1-facilitated uptake. PepT1 (SLC15A1) is a high-capacity H⁺-coupled transporter for di/tri-peptidesexpressed on the apical membrane of small-intestinal epithelia and induced in inflamed colon. KPV enters cells via PepT1, and PepT1 is required for KPV’s anti-inflammatory benefits in several preclinical models. PubMed

Implication: KPV’s cellular entry (rather than canonical MC1R signaling) appears to be the limiting step in inflamed mucosa, aligning with observations that KPV prevents colitis and CAC only when PepT1 is present. PMC

Intracellular signaling pathways

• NF-κB and cytokine modulation. Across epithelial and immune readouts, KPV reduces NF-κB activity and downstream cytokines (e.g., TNF-α), consistent with α-MSH-like anti-inflammatory signatures but realized post-uptake rather than strictly at the plasma membrane. PMC

• Barrier and wound-healing effects. Preclinical mucosal studies report improvements in barrier integrity and histologic healing; in skin models, α-MSH-related tripeptides oppose TNF-α–driven NF-κB activation in dermal fibroblasts, again consistent with anti-inflammatory endpoints. ScienceDirect

• MC1R-independent elements. At least part of KPV’s anti-inflammatory action is MC1R-independent, as shown in MC1R^e/e DSS colitis where KPV rescued survival and ameliorated pathology. The proximal intracellular targets responsible for MC1R-independent actions remain under investigation. Oxford Academic

CNS vs peripheral effects

• Peripheral predominance. The strongest evidence lies in peripheral tissues (intestine, skin). CNS penetrationand direct neuroendocrine actions are Not established for the free tripeptide; the literature focuses on mucosal/epithelial interfaces and immune modulation.

• Transport specificity. Because PepT1 is apical epithelial and up-regulated in inflamed colon, KPV research emphasizes local mucosal actions rather than systemic CNS effects. PubMed

Hormonal, metabolic, immune interactions

• Immune modulation. KPV attenuates pro-inflammatory cytokines and immune-cell recruitment in colitis models, with associated histopathologic improvement and body-weight recovery in T-cell transfer colitis. Oxford Academic

• Onco-inflammation interface. In the CAC setting, PepT1 facilitates carcinogenesis signals, and KPV delivered through PepT1 reduces tumor burden in mice; the effect disappears in PepT1-KO mice. PMC

Evidence grading (A–C)

• A (replicated in animals/cells): PepT1-mediated uptake; anti-inflammatory benefit in DSS and T-cell transfercolitis; MC1R-independent activity; nanodelivery dose-sparing in colon-targeted paradigms. PubMed+3PubMed+3PubMed+3

• B (translational plausibility): PepT1 induction in inflamed colon and CAC suggests disease-targeting rationale; comprehensive human PK/efficacy remains Not established. PMC+1

• C (hypothesis/uncertain): Systemic/cutaneous indications and long-term disease modification in humans—Not established; detailed intracellular targets beyond NF-κB remain uncertain.

Pharmacokinetics & Stability

ADME profile

• Absorption:

  • Intestinal epithelium: PepT1 is a high-capacity H⁺-coupled transporter for di/tri-peptides; KPV uptake increases where PepT1 is up-regulated (inflamed colon). PubMed

  • Skin/other mucosae: Direct transporters analogous to PepT1 are less characterized for KPV (data limited).

• Distribution: As a small, polar tripeptide, KPV is expected to have limited volume of distribution unless actively transported; most preclinical benefit is attributed to local mucosal exposure. (Human V_d: Not established.)

• Metabolism: Rapid peptidase degradation is expected systemically; nano-formulations and local delivery aim to limit systemic exposure and protect the peptide in transit. PubMed

• Excretion: Small peptide fragments would be cleared renally; detailed excretion fractions are Not established.

Plasma half-life & degradation pathways

• Plasma t½ (human): Not established.

• Experimental stability: Structure–modification studies (e.g., reductive amination, terminal acetylation/amidation) have been explored to improve stability while preserving activity. PMC

Stability in vitro & in vivo

• In vitro: KPV is stable over typical experimental time-courses in buffered systems; protease-rich environments shorten its life.

• In vivo: Local (colonic) delivery via hydrogel nanoparticles protects KPV and sharply reduces required dosesin rodent colitis. (Investigational nano-doses used in Laroui 2010/2012.) Gastro Journal+1

Storage/reconstitution considerations

The peer-reviewed literature does not provide universal, product-agnostic shelf-life or reconstitution curves for KPV; standard peptide handling (cold chain, protect from light, avoid repeated freeze–thaw) is generally applied in research. (Validated shelf-life data for commercial vials: Not established.)

Preclinical Evidence

Animal and in vitro studies (selected)

1) Colitis models & mucosal immunology

• DSS & T-cell transfer colitis (murine): KPV reduced disease activity, improved histology, and promoted weight recovery; survival benefits were observed even in MC1R-deficient mice, pointing to MC1R-independentmechanisms. (Investigational murine dosing used in study Kannengiesser 2008.) PubMed

• PepT1 dependence: KPV’s efficacy in colitis and prevention of CAC required PepT1; no benefit occurred in PepT1-KO mice given identical KPV regimens (investigational regimens used in Dalmasso 2008; Viennois 2016). PubMed+1

2) Nanoparticle delivery & dose-sparing

• Polysaccharide hydrogel nanoparticles targeted to the colon increased local drug availability and enabled dramatic dose reductions (reported in the 10³–10⁴-fold range in rats) for anti-inflammatory agents including KPV. (Investigational nano-doses used in Laroui 2010/2012.) PubMed+2Gastro Journal+2

3) Cutaneous and fibroblast systems

• In human dermal fibroblasts, α-MSH peptides and KPV derivatives dampened TNF-α–stimulated NF-κBactivation, consistent with a generalizable anti-inflammatory signature. (Investigational in-vitro concentrations used in Hill 2006.) ScienceDirect

4) Structure–activity relationships

• KPV analogs with terminal modifications can retain anti-inflammatory activity; medicinal-chemistry studies propose stability-enhancing changes while maintaining receptor-independent actions. PMC

Dose ranges tested (illustrative; all investigational)

• Free KPV in murine colitis: dose levels vary across studies (e.g., daily µmol·kg⁻¹ equivalents; route-specific), typically administered intrarectally, orally, or systemically depending on the model. (Investigational doses used in study Kannengiesser 2008; Dalmasso 2008.) PubMed+1

• Nanoparticle KPV: orders-of-magnitude lower than free peptide for comparable efficacy in rat/mouse colitis. (Investigational nano-doses used in Laroui 2010/2012.) Gastro Journal+1

Comparative efficacy/safety

• Efficacy: Robust preclinical evidence supports KPV’s anti-inflammatory activity in IBD models, with histologicand clinical improvements. PubMed

• Safety: No GLP-conformant long-term toxicology programs focused solely on KPV were identified; short-course rodent studies do not flag notable toxicity at investigational doses. (Long-term safety: Not established.)

Limitations

• Species & route differences complicate dose translation.

• Human PK and exposure–response data are absent.

• MC1R-independent mechanisms are not fully mapped; proximal intracellular targets remain to be conclusively identified.

Human Clinical Evidence

Phase I–III trials & registries

• A systematic search of ClinicalTrials.gov and the peer-reviewed literature found no completed Phase II/IIIrandomized trials dedicated to KPV as a single agent for any indication, and no registry-listed late-phase trialsfor KPV alone were identified as of September 26, 2025. (Not established.)

Observational/early translational signals

• Human evidence for KPV alone remains preclinical-leaning; much of the translational rationale derives from PepT1 up-regulation in human IBD and CAC specimens (biopsy-level expression), not from KPV-specificinterventional trials. PMC

Safety signals/adverse events in humans

• No systematically collected KPV-specific human safety dataset is available in peer-reviewed registries. Any safety inferences are indirect, drawn from class knowledge of di/tri-peptides, melanocortin fragments, and from the absence of overt toxicity in short-term rodent experimentation. (Not established.)

Comparative Context

Related peptides/approaches

• α-MSH (full peptide) and melanocortin agonists: upstream ligands of MC1R/MC3R/MC4R with broad anti-inflammatory and metabolic effects—but with pigmentary and CNS considerations in some contexts. PMC

• Melanocortin tripeptide analogs (KdPT, KP-D-V): designed for anti-inflammation with modified receptor interactions/stability. PMC+1

• Barrier-targeted strategies: PepT1-guided delivery or nanoparticle systems emphasize local epithelial uptakeand dose-sparing in inflamed colon. Gastro Journal

Advantages (research perspective)

• Small-molecule-like transport via PepT1;

• MC1R-independent anti-inflammation broadens applicability to non-pigmentary tissues;

• Dose-sparing with nanocarriers reduces systemic exposure in preclinical colitis. PubMed+2PubMed+2

Disadvantages / constraints

• Human efficacy and PK are Not established;

• Short peptide may have rapid systemic degradation;

• Mechanistic ambiguity persists beyond NF-κB suppression;

• Regulatory-grade safety/tox data are lacking.

Research category placement

• KPV is best classified as a PepT1-addressable, anti-inflammatory tripeptide tool for mucosal immunology and barrier research, with exploratory applications in dermatology and onco-inflammation models. PMC

Research Highlights

• Transporter-enabled pharmacology: PepT1 is both a gatekeeper and disease-target in inflamed colon, enabling selective epithelial uptake of KPV and therapeutic activity; PepT1 deletion abrogates KPV’s benefit. PubMed+1

• Receptor independence: KPV’s efficacy in MC1R-deficient colitis separates it from α-MSH’s classic MC1Raxis, implying distinct intracellular effectors after epithelial entry. PubMed

• Dose-sparing delivery: Colon-targeted nanoparticles allowed 10³–10⁴-fold reductions in required doses in rodent colitis, underscoring the value of formulation science for small peptides. Gastro Journal+1

• Onco-inflammation angle: In CAC models, KPV prevents tumorigenesis only when PepT1 is functional, linking inflammation control, transporter biology, and cancer risk. PMC

Conflicting/uncertain areas

• Upstream vs downstream targets: The extent to which KPV modulates MC1R or other membrane targets in vivoremains contested given MC1R-independent results. PubMed

• Extrapolation beyond mucosa: Signals in skin/dermis exist in vitro, but in vivo cutaneous efficacy data are lighter than for intestine. ScienceDirect

• Human translation: Efficacy, dose, PK, and chronic safety—Not established.

Potential Research Applications (no clinical claims; research-use framing)

1. PepT1-dependent uptake mapping.
   Quantify KPV transport kinetics across diseased vs healthy human colonoid models and PepT1-manipulatedepithelial monocultures; deploy inhibitors or siRNA/CRISPR to dissect transport dependence and post-uptakesignaling (NF-κB, inflammasome readouts). PubMed

2. Local-delivery optimization.
   Compare polysaccharide hydrogel nanoparticles, mucoadhesive capsules, and pH-triggered coatings for colon targeting; read out mucosal exposure, histologic healing, and multi-omics endpoints while minimizing systemic levels. (Nano-paradigm supported by Laroui 2010/2012.) Gastro Journal+1

3. Onco-inflammation interfaces.
   In CAC models, pair KPV with PepT1 expression mapping and single-cell RNA-seq to link transport, epithelial stress responses, and tumor microenvironment changes. PMC

4. Cutaneous anti-inflammation.
   Test KPV (and analogs) in UV- or irritant-induced dermatitis models; correlate NF-κB suppression in dermal fibroblasts/keratinocytes with in vivo edema/erythema scores and cytokine panels. ScienceDirect

5. Medicinal-chemistry variants.
   Evaluate terminal modifications (e.g., Ac-KPV, amide variants) and D-amino acid substitutions for protease resistance without losing PepT1 transport; screen for MC1R-independent activity in epithelial systems. PMC

Safety & Toxicology

Preclinical toxicity data

• General profile: Rodent colitis models report good short-term tolerability at investigational doses. No GLP-grade long-term toxicology packages dedicated to KPV were found. (Not established.)

• Nanocarrier safety: Colon-targeted hydrogel nanoparticles used with KPV were well tolerated in rats/mice over study durations; immunogenicity and chronic accumulation assessments require longer programs. Gastro Journal

Known/theoretical molecular risks

• Transporter specificity: Off-target uptake via other peptide transporters could occur in inflamed tissues beyond the gut (Unknown).

• Immune modulation: Long-term suppression of NF-κB in mucosa might impair host defense or wound remodeling under certain conditions (Not established for KPV).

• Onco-biology: While PepT1-enabled KPV reduced CAC in mice, the net impact on tumor immunosurveillanceacross tissues is Unknown.

Human safety observations

• KPV-specific human safety datasets (systematic AE capture, dose escalation, DDI, immunogenicity) are Not established as of this writing.

Limitations & Controversies

• Clinical evidence gap: No late-phase RCTs for KPV; human PK/PD unknown.

• Mechanistic uncertainty: MC1R-independence in colitis suggests alternative pathways; exact intracellular targets remain to be clarified beyond NF-κB and cytokine panels. PubMed

• Formulation dependence: Reported dose-sparing hinges on colon targeting; free peptide may underperform without PepT1-rich microenvironments. Gastro Journal

• Generalizability: Benefits in murine models may not translate directly to human IBD heterogeneity (genetics, microbiome, barrier phenotypes).

Future Directions

1. First-in-human PK/PD & safety.
   Conduct Phase I studies establishing single- and multiple-ascending dose KPV PK, tolerability, and exploratory biomarkers (fecal calprotectin, cytokines), preferably with colon-targeted delivery.

2. Mechanistic deconvolution.
   Use phosphoproteomics, transcriptional reporters, and CRISPR screens to map KPV’s intracellular targetspost-PepT1 uptake in human organoid systems.

3. Responder biology.
   Stratify preclinical models by PepT1 expression, microbiome state, and barrier integrity to identify predictorsof KPV response and minimize non-responders.

4. CMC & analytics.
   Develop validated LC-MS/MS assays for KPV and metabolites in biological matrices; quantify tissue exposureunder colon-targeted regimens and correlate with efficacy.

5. Comparative trials vs standards.
   In advanced models (and ultimately clinical studies), compare KPV or KPV-nano to reference anti-inflammatories using harmonized endpoints (histology, endoscopy scores, transcriptomic remission).

References

1. Kannengiesser K, et al. Melanocortin-derived tripeptide KPV has anti-inflammatory potential in murine models of inflammatory bowel disease. Inflamm Bowel Dis. 2008;14(3):324–331. PMID: 18092346. (MC1R-independent efficacy.) PubMed+1

2. Dalmasso G, et al. PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation. Gastroenterology.2008;134(5):1522–1532. PMID: 18061177. (Transporter dependence in epithelium/immune cells.) PubMed+1

3. Viennois E, et al. Critical role of PepT1 in promoting colitis-associated cancer and therapeutic benefits of the anti-inflammatory PepT1-mediated tripeptide KPV in a murine model. Cell Mol Gastroenterol Hepatol.2016;2(3):340–357. PMID: 27458604; PMCID: PMC4957955. (CAC prevention requires PepT1.) PubMed+1

4. Laroui H, et al. Drug-loaded nanoparticles targeted to the colon with polysaccharide hydrogel reduce colitis in a mouse model. Gastroenterology. 2010;138(3):843–853.e1–2. PMID: 19909746. (Colon targeting; dose-sparing paradigm.) PubMed

5. Laroui H, et al. Gastrointestinal delivery of anti-inflammatory nanoparticles. Adv Drug Deliv Rev/Gastroenterology derivative; 2012. PMID: 22568903. (Broader nano-delivery principles.) PubMed

6. Luger TA, et al. α-MSH-related peptides: a new class of anti-inflammatory and immunomodulating drugs? Exp Dermatol. 2007;16(8):616–623. PMCID: PMC2095288. (KPV as principal anti-inflammatory determinant.) PMC

7. Gravina AG, et al. The melanocortin system in inflammatory bowel diseases. Int J Mol Sci. 2023;24(13):10760. PMCID: PMC10378568. (Contemporary review; KPV rationale within α-MSH family.) PMC

8. Songok AC, et al. Structural modification of the tripeptide KPV by reductive “amination.” Pharmaceutics.2018;10(3):135. PMCID: PMC6023233. (Medicinal-chemistry variants.) PMC

9. Hill RP, et al. Melanocyte-stimulating hormone peptides inhibit TNF-α-stimulated NF-κB in human dermal fibroblasts. J Inflamm. 2006;3:1–12 (abstracted on SciDirect). (Cutaneous anti-inflammation with KPV derivatives.) ScienceDirect

10. Gastroenterology (Elsevier portal). PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation. Full-text abstract & methods context. (Access mirror.) Gastro Journal

11. IBD Journal (OUP/CCFA). Melanocortin-derived tripeptide KPV—anti-inflammatory potential. (Access mirror.) Oxford Academic

12. Cell Mol Gastro Hepatol / JCI citations page. Linking PepT1/KPV within CAC bibliographies. JCI

13. Pharmaceutics (MDPI). Molecular insights to structure–interaction of PepT1 and disease. 2023. (PepT1 expression and CAC link.) MDPI

14. Inflamm Bowel Dis. Ovid access note for the 2008 KPV colitis study. (Alternate source.) Ovid

Notes on amounts: Doses and regimens cited above are model-specific and reported as investigational in the respective studies.

⚠️ Disclaimer This peptide is intended strictly for laboratory research use. It is not FDA-approved or authorized for human use, consumption, or therapeutic application.