KPV

Product description

What is KPV?

KPV is a tripeptide consisting of the amino acids lysine-proline-valine (Lys-Pro-Val), constituting the C-terminal fragment of the α-melanocytostimulatory hormone (α-MSH). This sequence corresponds to positions 11-13 of full-length α-MSH and has been identified as the region responsible for most of the anti-inflammatory properties of this neuropeptide, while lacking broader hormonal effects related to skin pigmentation.

α-MSH is a thirteen-peptide product of the proteolytic processing of proopiomelanocortin (POMC), exhibiting broad protective, anti-inflammatory and antimicrobial effects. Studies have shown that the anti-inflammatory activity of α-MSH is mediated mainly by three N-terminal amino acids, and the KPV fragment retains - or even exceeds - the effectiveness of the full-length peptide in inhibiting inflammatory processes.

Structurally, KPV is one of the smallest biologically active anti-inflammatory peptides, with a molecular weight of approximately 342 Da. The simple structure and small particle size enable various routes of administration, including oral, topical and injection. Unlike many therapeutic peptides, KPV is stable in the gastrointestinal tract, which opens up the possibility of oral applications.

KPV attracts the attention of researchers due to its potential applications in the treatment of inflammatory bowel diseases (IBD), skin inflammation and as an alternative to classic anti-inflammatory drugs with a lower risk of side effects. The peptide is a naturally occurring fragment of an endogenous hormone, which suggests a favorable safety profile.

Mechanism of action

Inhibition of the NF-κB pathway - The key mechanism of KPV's anti-inflammatory effect is inhibition of the activation of the NF-κB transcription factor, a central regulator of pro-inflammatory gene expression. The peptide prevents the degradation of the IκB-α inhibitor by blocking the translocation of NF-κB into the cell nucleus and reducing the production of pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6.

Transport by PepT1 - Studies have shown that the anti-inflammatory effects of KPV are mediated by the di/tripeptide transporter PepT1 (hPepT1) and not by melanocortin receptors. PepT1 is normally expressed in the small intestine and induced in the colon during inflammatory bowel diseases. Transport of KPV into cells by PepT1 leads to intracellular accumulation of the peptide and inhibition of inflammatory signaling pathways.

Inhibition of the MAPK cascade - In addition to NF-κB, KPV also inhibits the activation of MAP kinases (mitogen-activated protein kinases), which are involved in the transmission of pro-inflammatory signals. Double inhibition of NF-κB and MAPK pathways provides comprehensive anti-inflammatory effects.

Reduction of cytokine secretion - KPV reduces the secretion of pro-inflammatory cytokines by intestinal epithelial cells and immune cells. At nanomolar concentrations, the peptide effectively reduces the production of IL-8 and other inflammatory mediators in cytokine-stimulated cells.

Melanocortin receptor-independent mechanism - Unlike full-length α-MSH, KPV does not bind to the MC1R, MC3R, or MC5R melanocortin receptors and does not compete with α-MSH for these receptors. The anti-inflammatory effect is preserved in mice with non-functional MC1R, supporting an alternative mechanism of action.

Directions of scientific research

Research on KPV mainly focuses on its potential use in inflammatory bowel diseases and skin inflammation.

Inflammatory bowel disease (IBD)

In studies on mouse models of enteritis (DSS-induced colitis, TNBS-induced colitis), oral administration of KPV significantly reduced the severity of disease symptoms. The peptide reduced weight loss, colonic myeloperoxidase activity, and histological signs of inflammation. In the study by Kannengiesser et al. (2008) KPV demonstrated significant anti-inflammatory effects in two models of intestinal inflammation, and these effects were at least partially independent of MC1R signaling.

Molecular mechanisms in intestinal cells

Studies on human intestinal epithelial cells (Caco2-BBE, HT29-Cl.19A) showed that nanomolar concentrations of KPV inhibit the activation of NF-κB and MAPK signaling pathways and reduce the secretion of pro-inflammatory cytokines. Dalmasso et al. (2008) confirmed that KPV is transported into cells by hPepT1 and that its anti-inflammatory effect depends on the expression of this transporter. Since PepT1 expression is increased in intestinal inflammation, this creates the possibility of selective delivery of the peptide to inflamed sites.

Nanoparticle delivery systems

Due to the potential degradation of the peptide in the gastrointestinal tract, advanced KPV delivery systems have been developed. Xiao et al. (2017) demonstrated that KPV-loaded hyaluronic acid functionalized nanoparticles effectively alleviate ulcerative colitis through targeted delivery to inflamed tissues and activated macrophages.

Wound healing and skin inflammation

Research suggests potential uses for KPV in wound healing and the treatment of inflammatory skin conditions such as eczema, psoriasis and atopic dermatitis. The peptide can accelerate reepithelialization and reduce inflammation at the site of tissue damage.

Scientific context

KPV belongs to the melanocortin peptide family, which also includes:

• α-MSH - full-length hormone, KPV precursor, with anti-inflammatory and pigmentogenic effects
• ACTH - adrenocorticotropic hormone, also POMC
• K(D)PT - a related tripeptide with similar anti-inflammatory properties

Compared to full-length α-MSH, KPV offers several potential advantages as a therapeutic candidate:

• Simplicity - smaller molecule, easier to synthesize and formula
• Selectivity - maintains anti-inflammatory effect without affecting pigmentation
• Stability - shows stability in the conditions of the gastrointestinal tract
• Bioavailability - can be administered orally thanks to transport by PepT1

KPV differs from classic anti-inflammatory drugs (NSAIDs, corticosteroids) in its mechanism of action and potentially more favorable safety profile. As a naturally occurring fragment of an endogenous hormone, the peptide is unlikely to cause the typical side effects associated with long-term anti-inflammatory therapy, such as adrenal suppression, osteoporosis or the risk of gastrointestinal bleeding.

Research safety profile

General tolerance - In preclinical studies, KPV showed a very favorable safety profile. As a small, naturally occurring fragment of α-MSH, the peptide is generally well tolerated and does not cause the systemic complications typical of more potent immunosuppressive drugs.

Oral tolerance - Animal studies demonstrate KPV stability in the gastrointestinal tract without toxic effects at typical test doses.

Topical safety - Cream and gel preparations for topical use did not cause significant irritation or local adverse reactions.

Injection use - No serious systemic toxicity has been reported in preclinical studies even at relatively high doses (mg/kg).

No immunosuppression - Unlike corticosteroids, KPV regulates inflammation without suppressing immune function, which reduces the risk of long-term complications such as adrenal suppression, tissue breakdown, and increased risk of infection.

Regulatory Status - KPV is not approved by the FDA or other major regulatory agencies for clinical use. The peptide remains at the stage of preclinical and early clinical trials. The FDA considered KPV in the context of a pharmaceutical formulation substance, expressing concerns about the immunogenicity of synthetic peptides and contaminants.

Bibliography - latest scientific research

1. Dalmasso G et al. PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation. Gastroenterology. 2008;134(1):166-178. PubMed
2. 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. PubMed
3. Xiao B et al. Orally Targeted Delivery of Tripeptide KPV via Hyaluronic Acid-Functionalized Nanoparticles Efficiently Alleviates Ulcerative Colitis. Mol Ther. 2017;25(7):1628-1640. PMC
4. Böhm M et al. α-MSH related peptides: a new class of anti-inflammatory and immunomodulating drugs. Ann Rheum Dis. 2007;66 Suppl 3:iii52-55. PMC
5. Luger TA et al. New insights into the functions of alpha-MSH and related peptides in the immune system. Ann N Y Acad Sci 2003;994:133-140. PubMed
6. 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. PubMed
7. 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. PubMed
8. Land SC. 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. Int J Physiol Pathophysiol Pharmacol. 2012;4(2):59-73. PubMed
9. Brzoska T et al. α-Melanocyte-stimulating hormone and related tripeptides: biochemistry, antiinflammatory and protective effects in vitro and in vivo, and future perspectives for the treatment of immune-mediated inflammatory diseases. Endocr Rev. 2008;29(5):581-602. PubMed
10. Cutuli M et al. Antimicrobial effects of alpha-MSH peptides. J Leukoc Biol. 2000;67(2):233-239. PubMed