KPV

KPV Research

What is the research background of KPV?

KPV is a tripeptide derived from α-melanocyte-stimulating hormone (α-MSH). α-MSH is a polypeptide hormone with multiple biological functions, playing an important role in regulating skin pigmentation, immune regulation, and other aspects. As a part of α-MSH, KPV has been isolated and deeply studied. Although some progress has been made in the medical field in recent years, the treatment options for inflammatory bowel disease (IBD) are still unsatisfactory, and the surgery rate remains high. Therefore, finding new and effective treatment methods has become an urgent task. IBD includes ulcerative colitis, Crohn's disease, etc., which are characterized by chronic intestinal inflammation and seriously affect the quality of life of patients. Current treatment methods include drug therapy and surgical treatment, but both have certain limitations. In recent years, the anti-inflammatory effects of melanocortin peptides such as α-MSH have been described in dextran sulfate sodium (DSS) colitis in mice. This provides a clue for studying the anti-inflammatory potential of KPV. α-MSH has functions such as immune regulation and inflammation alleviation, and the tripeptide KPV derived from it is also considered to possibly have similar anti-inflammatory properties.

What is the mechanism of action of KPV?

Mechanism of action in ulcerative colitis

Improving stability and rectal administration convenience: 

KPV (Lys-Pro-Val) is a tripeptide derived from α-MSH (α-melanocyte-stimulating hormone) and has anti-inflammatory effects against colitis. However, the KPV solution is very unstable during rectal administration, affecting its therapeutic effect. In the study, cysteamine-grafted γ-polyglutamic acid (SH-PGA) was synthesized by combining cysteamine with the carboxyl group of γ-PGA. Without using a cross-linking agent, a 4% polymer content SH-PGA hydrogel was formed through the self-cross-linking of sulfhydryl groups. The KPV/SH-PGA hydrogel showed an elastic modulus (G') higher than the corresponding viscous modulus (G'') at 0.01-10 Hz, exhibiting good mechanical stability and shear thinning behavior, which is beneficial for rectal administration. At the same time, the stability of KPV in the SH-PGA hydrogel was significantly enhanced. Only 30% of KPV was released from the KPV/SH-PGA hydrogel within 20 minutes, followed by a continuous release behavior^[1].

Alleviating colitis symptoms: 

Through experiments on rats with ulcerative colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS), the enhanced therapeutic effect of the KPV/SH-PGA hydrogel on colitis was confirmed. After rectal administration of the KPV/SH-PGA hydrogel, colitis symptoms including weight loss and disease activity index scores were significantly alleviated. In addition, treatment with the KPV/SH-PGA hydrogel prevented the shortening of the colon in rats injected with TNBS and reduced the level of colonic myeloperoxidase. After treatment with the KPV/SH-PGA hydrogel, the morphology of the colon, including the epithelial barrier, crypts, and intact goblet cells, was restored. At the same time, the KPV/SH-PGA hydrogel reduced the expression of pro-inflammatory cytokines such as tumor necrosis factor α and interleukin 6^[1].

Mechanism of action in mouse models of inflammatory bowel disease

DSS colitis model: In the DSS colitis model, treatment with KPV led to earlier recovery and significantly enhanced weight recovery. Histologically, the inflammatory infiltration in KPV-treated mice was significantly reduced, which was confirmed by the significant decrease in the activity of myeloperoxidase (MPO) in the colonic tissue after KPV treatment^[2].

CD45RB (hi) transfer colitis model: 

Supporting the above findings, KPV treatment of transferred colitis led to disease recovery, weight recovery, and a reduction in inflammatory changes from a histological perspective^[2].

MC1Re/e mouse model: 

In mice expressing a non-functional melanocortin-1 receptor (MC1Re/e), KPV treatment saved all animals in the treatment group from death during DSS colitis. This indicates that the anti-inflammatory effect of KPV seems to be at least partially independent of MC1R signaling^[2].

Mechanism of action in bronchial epithelial cell inflammation

Inhibiting NF-κB signaling: 

In immortalized human bronchial epithelial cells, the melanocortin-related peptide KPV and the agonist α-MSH of airway epithelium (MC3R) inhibited NF-κB signaling by inhibiting the nuclear import of p65RelA and activating epithelial MC3R, respectively. Specifically, the effect of KPV is related to its nuclear import, which can inhibit the nuclear translocation of p65RelA labeled with YFP. At the same time, the binding sites of KPV and Imp-α/β are on p65RelA, possibly involving blocking importin-α armadillo domains 7 and 8 ^[3].

Mechanism of action in chemotherapy-induced oral mucositis

Antibacterial, anti-inflammatory, and repair effects: 

Using temperature-sensitive PLGA-PEG-PLGA (PPP) as the matrix and epigallocatechin-3-gallate (EGCG) with inherent antibacterial activity as the adhesion enhancer, an in-situ mucosal adhesive hydrogel (PPP_E) was successfully prepared. The tripeptide KPV was dissolved in the cold PPP_2% E precursor solution as a model drug to prepare the KPV@PPP_2% E hydrogel. The anti-inflammatory activity and the potential to promote cell migration of KPV in the PPP-2% E hydrogel were well maintained. In addition, the KPV@PPP_2% E had a strong antibacterial effect against Staphylococcus aureus. When the KPV@PPP_2% E hydrogel was applied to the gingival mucosa of rats with chemotherapy-induced oral mucositis, it could rapidly transform into a hydrogel and adhere to the wound surface for 7 hours, greatly improving the food intake and weight recovery of the rats. At the same time, by promoting the expression of CK10 and PCNA, the KPV@PPP_E hydrogel also well repaired the tissue morphology of the ulcerated gingiva. In addition, the KPV@PPP_2% E hydrogel significantly inhibited inflammatory cytokines including IL-1β and TNF-α, and at the same time upregulated IL-10 ^[4].

Source:PubMed^[5]

 What are the clinical application cases of KPV drugs?

Treatment of ulcerative colitis

Administration through self-crosslinking hydrogel: 

In a study, cysteamine-grafted γ-polyglutamic acid (SH-PGA) was synthesized and made into a hydrogel to stabilize the tripeptide KPV^[1]. The KPV/SH-PGA hydrogel showed good therapeutic effects in a rat model of ulcerative colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). Specifically, after rectal administration, colitis symptoms such as weight loss and disease activity index scores were significantly alleviated, and it could also prevent the shortening of the colon in rats injected with TNBS and reduce the level of colonic myeloperoxidase. At the same time, the morphology of the colon, including the epithelial barrier, crypts, and intact goblet cells, was restored after treatment with the KPV/SH-PGA hydrogel, and the hydrogel also reduced the expression of pro-inflammatory cytokines such as tumor necrosis factor α and interleukin 6.

Administration through dual-network hydrogel: 

Another study constructed a dual-network hydrogel (PMSP) formed by maleated γ-polyglutamic acid and thiolated γ-polyglutamic acid through thiol-maleimide cross-linking and self-oxidation of thiols ^[5]. This hydrogel can specifically adhere to the inflamed mucosa rather than the healthy mucosa, and has good mechanical strength and biological adhesion. KPV, as a model drug, is easily captured by PMSP through electrostatic interaction, thus maintaining its biological activity for a longer time under high-temperature conditions. In rats with colitis induced by TNBS, after rectal administration of PMSP-KPV, the alleviating effect of KPV on colitis was significantly improved, and the epithelial barrier of the colon was effectively restored. In addition, PMSP-KPV also regulated the intestinal flora and significantly increased the abundance of beneficial microorganisms in the intestine.

For chemotherapy-induced oral mucositis

An in-situ mucosal adhesive hydrogel (PPP_E) was prepared using temperature-sensitive PLGA-PEG-PLGA (PPP) as the matrix and epigallocatechin-3-gallate (EGCG) as the adhesion enhancer ^[4]. The tripeptide KPV was dissolved in the cold PPP_2% E precursor solution as a model drug to prepare the KPV@PPP_2% E hydrogel. This hydrogel has anti-inflammatory, antibacterial, and repair effects on chemotherapy-induced oral mucositis. Specifically, it can maintain the anti-inflammatory activity of KPV and the potential to promote cell migration, and has a strong antibacterial effect against Staphylococcus aureus. After administration to the gingival mucosa of rats with chemotherapy-induced oral mucositis, the PPP_2% E precursor solution rapidly transformed into a hydrogel and adhered to the wound surface for 7 hours. Treatment with the KPV@PPP_2% E hydrogel greatly improved the food intake and weight recovery of the rats, promoted the expression of CK10 and PCNA, well repaired the tissue morphology of the ulcerated gingiva, and at the same time significantly inhibited inflammatory cytokines such as IL-1β and TNF-α, and upregulated the expression of IL-10. This hydrogel also has an antibacterial effect on gingival ulcer wounds infected with methicillin-resistant Staphylococcus aureus (MRSA), and significantly inhibits the infiltration of inflammatory cells into the submucosal tissue.

Treatment of inflammatory bowel disease

Some studies have shown that KPV may be a new therapeutic drug for inflammatory bowel disease (IBD) ^[6]. In human intestinal epithelial cells (Caco2-BBE and HT29-Cl.19A) and human T cells (Jurkat), after stimulation with pro-inflammatory cytokines, the addition of KPV can inhibit the activation of NF-κB and MAP kinase inflammatory signaling pathways and reduce the secretion of pro-inflammatory cytokines. The study found that KPV acts through hPepT1 expressed in immune and intestinal epithelial cells. In addition, in mouse models of colitis induced by dextran sulfate sodium (DSS) and TNBS, oral administration of KPV can reduce the expression of pro-inflammatory cytokines and the incidence of colitis.

In conclusion, as a bioactive substance with great potential, KPV shows unique advantages in the treatment of various diseases. In the field of inflammatory bowel disease, whether in mouse model experiments or in the exploration of different administration methods for ulcerative colitis, KPV can effectively reduce inflammatory infiltration, improve tissue morphology, regulate cytokine expression, and exert significant anti-inflammatory effects through mechanisms such as PepT1 transport. In the treatment of chemotherapy-induced oral mucositis, the hydrogel containing KPV prepared with a specific matrix and adhesion enhancer can not only maintain its anti-inflammatory and cell migration-promoting activities but also has a powerful antibacterial ability, significantly improving the related symptoms of rats and promoting tissue repair. Although the current clinical application cases of KPV are still limited, the existing research results fully demonstrate its therapeutic value. In the future, if breakthroughs can be achieved in in-depth research on improving drug stability and delivery efficiency, expanding clinical indications, and strengthening clinical monitoring and management, KPV is expected to bring more high-quality and efficient treatment options for more patients and play a more important role in clinical treatment.

Relevant Citations

[1] Sun J, Xue P, Liu J, et al. Self-Cross-Linked Hydrogel of Cysteamine-Grafted γ-Polyglutamic Acid Stabilized Tripeptide KPV for Alleviating TNBS-Induced Ulcerative Colitis in Rats[J]. Acs Biomaterials Science & Engineering, 2021,7(10):4859-4869.DOI:10.1021/acsbiomaterials.1c00792.

[2] Konnengiesser K, Maaser C, Heidemann J, et al. Melanocortin-derived tripeptide KPV has anti-inflammatory potential in murine models of inflammatory bowel disease[J]. Inflammatory Bowel Diseases, 2008,14(3):324-331.DOI:10.1002/ibd.20334.

[3] Land S C. 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.[J]. International Journal of Physiology, Pathophysiology and Pharmacology, 2012,4(2):59-73. https://pubmed.ncbi.nlm.nih.gov/22837805/

[4] Shao W, Chen R, Lin G, et al. In situ mucoadhesive hydrogel capturing tripeptide KPV: the anti-inflammatory, antibacterial and repairing effect on chemotherapy-induced oral mucositis[J]. Biomaterials Science, 2021,10(1):227-242.DOI:10.1039/d1bm01466h.

[5] Zhao Y, Xue P, Lin G, et al. A KPV-binding double-network hydrogel restores gut mucosal barrier in an inflamed colon[J]. Acta Biomaterialia, 2022,143:233-252.DOI:10.1016/j.actbio.2022.02.039.

[6] Dalmasso G, Charrier-Hisamuddin L, Nguyen H T T, et al. PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation[J]. Gastroenterology, 2008,134(1):166-178.DOI:10.1053/j.gastro.2007.10.026.