KPVresearch overview.

Overview

KPV is the tripeptide Lys-Pro-Val. It matches residues 11 to 13 at the C-terminus of α-⁠melanocyte-stimulating hormone (α-⁠MSH), a 13-residue peptide cut from the precursor pro-opiomelanocortin. Interest in the fragment grew out of work on α-⁠MSH itself. In 1989, Hiltz and Lipton described the C-terminal tripeptide as the part of α-⁠MSH thought to account for activity seen with the full hormone in earlier fever models, and tested α-⁠MSH(11⁠–⁠13) in a mouse ear-swelling model ¹.

A 2008 review by Brzoska and colleagues summarises the α-⁠MSH literature and the later work on KPV and a related tripeptide, KdPT ⁵. The primary KPV literature is small. Most of it comes from melanocortin research groups and from a group studying peptide transport in intestinal epithelial cells ^2,3,4.

Published work falls into three broad lines: inflammation-related measures in mouse models, whether KPV acts through melanocortin receptors as the parent hormone does, and how the peptide enters cells and relates to NF-κB signalling ^2,3,4,6.

Structure and chemistry

KPV is a linear peptide of three L-amino acids: L-lysyl-L-prolyl-L-valine. Molecular formula C16H30N4O4, molecular weight 342.4 g/mol, CAS 67727-97-3. In native α-⁠MSH the final valine carries a C-terminal amide. The tripeptide described by this formula is the free acid, with a carboxyl group at the C-terminus.

With a free N-terminal amine, the lysine side-chain amine and one carboxyl group, KPV carries a net positive charge at neutral pH. The central proline restricts the flexibility of the backbone, and peptide bonds involving proline are cut by fewer common peptidases.

Its small size matters for one line of research. Di- and tripeptides are substrates of PepT1, a proton-coupled peptide transporter expressed in the small intestine. Dalmasso et al. (2008) tested whether KPV is carried by PepT1 into intestinal epithelial cells and reported that it was ³. Land (2012) noted that KPV has the features of a minimal nuclear localisation sequence, a short basic motif recognised by importin-α, and tested that idea in airway epithelial cells ⁶.

Brzoska et al. also describe KdPT (Lys-D-Pro-Thr), a tripeptide that corresponds to residues 193 to 195 of interleukin-1β, and discuss it alongside KPV ⁵. The two are often compared in the literature but are distinct compounds.

Mechanisms investigated

No receptor for KPV has been established. Several studies have asked whether it works through melanocortin receptors, as α-⁠MSH does, and their findings have mostly pointed away from that route.

• Melanocortin receptors. In a mouse model of urate crystal-induced peritonitis, Getting et al. (2003) reported that KPV reduced the accumulation of polymorphonuclear leukocytes in the peritoneal cavity. This was not blocked by the MC3/MC4 receptor antagonist SHU9119, and it was also seen in IL-1β-⁠induced peritonitis and in mice with a non-functional MC1 receptor. The authors concluded that KPV was unlikely to act through melanocortin receptors and proposed inhibition of interleukin-1β functions instead ².
• Macrophage assays. In the same study, α-⁠MSH and melanotan II reduced the release of KC and IL-1β from activated macrophages in vitro, while KPV did not ².
• Peptide transport and NF-κB. Dalmasso et al. (2008) reported that KPV was taken up through PepT1 and was associated with lower NF-κB and MAP kinase signalling in intestinal epithelial and immune cells ³.
• Mouse colitis models. Kannengiesser et al. (2008) studied DSS-induced colitis and CD45RBhi T cell transfer colitis in mice. They reported lower myeloperoxidase activity and fewer inflammatory infiltrates in colonic tissue, and also studied mice with a non-functional MC1 receptor (e/e). They described the effects as partly independent of MC1R signalling ⁴. Dalmasso et al. also measured disease activity indices in DSS- and TNBS-induced colitis models in mice ³.
• Nuclear import. In immortalised human bronchial epithelial cells (16HBE14o-), Land (2012) measured NF-κB reporter activity and chemokine secretion after stimulation with TNFα or respiratory syncytial virus. KPV was associated with its own nuclear import, stabilisation of IκBα and reduced nuclear translocation of the p65RelA subunit. Competition assays suggested an interaction at the importin-α3 binding site on p65RelA ⁶.

Research areas

• Ear-swelling response in mice, the first KPV study (animal) ¹
• Crystal- and IL-1β-⁠induced peritonitis and melanocortin receptor dependence in mice (animal) ²
• PepT1 transport and NF-κB signalling in intestinal cells (in vitro) ³
• Chemically induced and T cell transfer colitis models in mice (animal) ^3,4
• NF-κB nuclear import in human bronchial epithelial cells (in vitro) ⁶
• α-⁠MSH and related tripeptides, including KdPT (review) ⁵

Limits of the evidence

All of the primary evidence summarised here is preclinical, from mouse models and cell lines. Outcomes were leukocyte counts, enzyme activity, histology scores, cytokine levels and reporter-gene signals. This summary did not identify published controlled studies of KPV in people in the indexed literature.

The proposed mechanisms differ from study to study. Getting et al. pointed to interleukin-1β functions ², Dalmasso et al. to PepT1 uptake and intracellular signalling ³, and Land to interference with NF-κB nuclear import ⁶. These came from different cell types and models and have not been combined into a single, tested mode of action.

The literature is small and concentrated. Several authors of the 2008 colitis study also wrote the main review cited here ^4,5, so there are fewer independent sources than the reference count suggests. Study designs differ in model, timing and route, and a finding from one design should not be assumed to carry over to another.

OzPept’s KPV is a research chemical, not a medicine, and is not for human use.

Key studies

1. 1989Animal

   Ear-swelling model in mice ¹

2. 2003Animal

   Peritonitis models and melanocortin receptor dependence ²

3. 2008In vitro

   PepT1 transport and NF-κB signalling in intestinal cells ³

4. 2008Animal

   DSS and T cell transfer colitis in mice ⁴

5. 2008Review

   α-⁠MSH and related tripeptides ⁵

6. 2012In vitro

   NF-κB nuclear import in bronchial epithelial cells ⁶

Questions

References

1. Hiltz ME, Lipton JM. Antiinflammatory activity of a COOH-terminal fragment of the neuropeptide alpha-MSH. FASEB J. 1989;3(11):2282-2284. Source
2. Getting SJ, Schiöth HB, Perretti M. Dissection of the anti-inflammatory effect of the core and C-terminal (KPV) alpha-melanocyte-stimulating hormone peptides. J Pharmacol Exp Ther. 2003;306(2):631-637. Source
3. Dalmasso G, Charrier-Hisamuddin L, Nguyen HT, Yan Y, Sitaraman S, Merlin D. PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation. Gastroenterology. 2008;134:166-178. Source
4. Kannengiesser K, Maaser C, Heidemann J, 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. Source
5. Brzoska T, Luger TA, Maaser C, Abels C, Böhm M. Alpha-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. Source
6. 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). Source