Description of KPV

KPV, a tripeptide composed of lysine, proline, and valine, exhibits potent anti-inflammatory properties, although its mechanisms of action have remained elusive. Studies aimed to investigate the role of PepT1, a di/tripeptide transporter, in mediating the anti-inflammatory effects of KPV in intestinal epithelial and immune cells. Results demonstrate that nanomolar concentrations of KPV inhibit NF-kappaB and MAP kinase inflammatory signaling pathways, leading to a reduction in pro-inflammatory cytokine secretion. Notably, KPV acts through PepT1 expressed in both immune and intestinal epithelial cells. Furthermore, oral administration of KPV reduces the incidence of colitis induced by dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS), highlighting its potential as a therapeutic agent for inflammatory bowel disease (IBD). The peptide was studied also for wound healing, scar formation, and other mostly anti-inflammatory properties.

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Research Confirmed Effects

1. KPV and Intestinal Inflammation

Mice treated with KPV display markedly diminished colonic infiltration and maintain normal colon lengths compared to control counterparts, underscoring its potential efficacy in mitigating inflammatory conditions. Notably, KPV's impact seems concentrated in settings of heightened inflammation, with minimal effect on normal tissue. This selectivity is attributed to its utilization of PepT1, a transporter upregulated during inflammatory states, suggesting KPV's suitability as a prophylactic or maintenance medication for inflammatory bowel disease (IBD). Furthermore, insights into KPV's mechanism of action propose a novel approach to drug delivery, targeting proteins modulated in disease conditions to concentrate drug activity. This approach holds promise for reducing the dosage of drugs with severe side effects and developing therapeutics tailored to specific disease states.

Professor Didier Merlin's investigations into KPV's gastrointestinal benefits have revealed its potential to enter colonic cells via PepT1, predominantly expressed during inflammatory states, elucidating its enhanced efficacy in inflamed settings. This finding not only supports KPV's candidacy as a therapeutic agent for IBD but also unveils a paradigm for drug delivery, exploiting alterations in protein expression to enhance drug localization and efficacy. Such targeted delivery strategies offer the prospect of minimizing drug dosages with adverse effects while maximizing therapeutic impact, heralding a new frontier in precision medicine for diverse disease states.

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2. KPV and Its Anti-Inflammatory Properties

Studies investigating the effect of α-MSH and related tripeptides, such as KPV, on fever and inflammation underscore their potential as anti-inflammatory agents. Specifically, α-MSH has exhibited potent anti-inflammatory and protective effects both in vitro and in vivo, impacting various pathways involved in inflammation regulation and protection. While α-MSH presents pigmentary concerns, its C-terminal tripeptide, KPV, has emerged as a promising alternative for anti-inflammatory therapy, devoid of pigmentary action yet preserving anti-inflammatory efficacy. Moreover, K(D)PT, a derivative of KPV, has also demonstrated potent anti-inflammatory effects, offering further therapeutic potential for immune-mediated inflammatory diseases affecting the skin, bowel, eyes, and joints.

Research spanning decades has elucidated the anti-inflammatory properties of KPV and its parent molecule, α-MSH, in a diverse array of inflammatory conditions, including fever, dermatitis, vasculitis, arthritis, and gastrointestinal inflammation. While α-MSH remains the most effective anti-inflammatory agent, its pigmentary side effects pose limitations. However, KPV's comparative lack of side effects suggests its potential as a safer alternative, albeit with slightly reduced potency. Notably, while KPV may be less potent than α-MSH, it still exerts considerable anti-inflammatory effects, particularly in mitigating immediate inflammatory responses. Ongoing research aims to uncover the precise mechanisms underlying these differential responses, providing insights into immune modulation and inflammation regulation.

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3. KPV and Wound Healing

The synthesis and evaluation of His-Phe-Arg-Trp-NH2 and its derivatives have revealed promising antifungal properties, particularly against Cryptococcus neoformans, suggesting a potential therapeutic avenue in combating fungal infections. These tetrapeptides exhibit antifungal activity akin to alpha-melanocyte-stimulating hormone (α-MSH), and theoretical calculations have elucidated their biologically relevant conformation and minimal structural requirements for antifungal response, guiding future compound design. Moreover, α-MSH and its derivatives, like KPV, have garnered interest for their implications in wound healing, particularly in minimizing scar formation and fostering a more regenerative healing process.

Recent studies highlight the potential of α-MSH analogues, such as KPV, in improving wound healing outcomes by reducing inflammation and promoting scarless healing. Alpha-MSH's anti-inflammatory activity, mediated via the melanocortin 1 receptor (MC-1R), has been associated with its ability to modulate immune responses and enhance tissue repair. Analogues like KPV offer anti-inflammatory and antimicrobial properties, presenting a promising therapeutic approach for wound care without inducing undesirable pigmentation or inhibiting the body's natural defense mechanisms against infection. Furthermore, ongoing research explores the structural basis of KPV's antifungal effects, suggesting its potential as a structural model for the development of novel antifungal therapeutics with improved efficacy and selectivity.

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4. KPV and Scar Formation

Skin wound healing is a complex process in adult mammals, often resulting in scar tissue formation. Alpha-melanocyte-stimulating hormone (α-MSH) is distributed widely in the central nervous system and skin, exhibiting strong anti-inflammatory activity. The study aimed to assess whether intraperitoneal injection of α-MSH before skin wounds could reduce inflammation and enhance wound healing in adult mice. Adult mice received an injection of 1 mg/kg of α-MSH before creating skin wounds. Wound healing was evaluated macroscopically and microscopically over 60 days. α-MSH reduced leukocytes, mast cells, and fibroblasts at 3 and 7 days post-injury, while also decreasing scar area and improving collagen fiber organization at days 40 and 60, indicating its potential to promote a more regenerative wound healing pathway.

The research on modulatory effects of NDP-MSH, analogue of α-MSH, in regenerating rat livers post partial hepatectomy (PH) reveals its potential to influence liver molecular changes induced by surgery. NDP-MSH treatment significantly altered the expression of various transcripts, including chemokines, receptors, and cell cycle mediators, enhancing critical signaling pathways like the interleukin-6 (IL-6)/signal transducer and activator of transcription (STAT)/suppressor of cytokine signaling (SOCS) axis. While NDP-MSH did not substantially affect the final organ regeneration, it exerted subtle influences on hepatocyte replication and gene expression, suggesting its potential salutary effects during liver regeneration.

In experimental heart transplantation, NDP-alpha-MSH, a synthetic analogue of alpha-melanocyte-stimulating hormone (α-MSH), demonstrated protective activity by influencing various molecular pathways associated with heart function preservation. The peptide induced expression of cytoskeleton proteins, intracellular kinases, and transcription regulators while repressing immune and inflammatory mediators, leading to down-regulation of oxidative stress response and up-regulation of ion channels and metabolic pathways. These findings suggest that NDP-alpha-MSH could enhance the outcome of organ transplantation by preserving heart function through its broad effect on multiple pathways, including both Ag-dependent and -independent injury.

Additionally, research on acute lung injury induced by bleomycin instillation in rats highlights the therapeutic potential of NDP-alpha-MSH in reducing inflammation and pulmonary edema. The peptide treatment mitigated bleomycin-induced transcriptional alterations in genes involved in stress response, inflammation, and fluid homeostasis, leading to a significant reduction in interstitial edema and down-regulation of proinflammatory and profibrotic factors.

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5. KPV and Alpha-MSH

α-Melanocyte-stimulating hormone (α-MSH) has emerged as a potent anti-inflammatory mediator, acting via melanocortin receptors (MC-Rs) expressed in various tissues. It modulates inflammatory responses through pathways like NF-κB activation, cytokine expression, and T-cell activity. While effective, its pigment-inducing capacity limits its therapeutic use. However, its C-terminal tripeptide, KPV, preserves anti-inflammatory properties without inducing pigmentation. Despite lacking MC-R binding motifs, KPV exhibits significant anti-inflammatory effects, making it a promising candidate for peptide therapy in immune-mediated inflammatory diseases like skin conditions, bowel diseases, asthma, and arthritis.

Studies comparing KPV with core MSH peptides reveal distinct anti-inflammatory mechanisms. Unlike core peptides, KPV's effects are not mediated through MC-Rs, suggesting alternative pathways such as IL-1β inhibition. Moreover, transdermal delivery studies highlight KPV's potential for diverse administration routes. While alpha-MSH is more potent, KPV's lack of side effects and ease of administration make it a preferable option. Its broad anti-inflammatory effects and multiple administration routes offer versatility in targeting different areas of the body for treatment, promising significant advancements in inflammatory disorder management.

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References

1. G. Dalmasso et al., “PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation”, 2008
2. M. E. Hiltz and J. M. Lipton, “Antiinflammatory activity of a COOH-terminal fragment of the neuropeptide alpha-MSH,” FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol., vol. 3, no. 11, pp. 2282–2284, Sep. 1989.
3. K. Kannengiesser et al., “Melanocortin-derived tripeptide KPV has anti-inflammatory potential in murine models of inflammatory bowel disease,” Inflamm. Bowel Dis., vol. 14, no. 3, pp. 324–331, Mar. 2008, doi: 10.1002/ibd.20334.
4. B. Xiao et al., “Orally Targeted Delivery of Tripeptide KPV via Hyaluronic Acid-Functionalized Nanoparticles Efficiently Alleviates Ulcerative Colitis,” Mol. Ther. J. Am. Soc. Gene Ther., vol. 25, no. 7, pp. 1628–1640, 05 2017, doi: 10.1016/j.ymthe.2016.11.020.
5. G. Dalmasso, L. Charrier-Hisamuddin, H. T. T. Nguyen, Y. Yan, S. Sitaraman, and D. Merlin, “PepT1-Mediated Tripeptide KPV Uptake Reduces Intestinal Inflammation,” Gastroenterology, vol. 134, no. 1, pp. 166–178, Jan. 2008, doi: 10.1053/j.gastro.2007.10.026.
6. D. B. Richards and J. M. Lipton, “Effect of alpha-MSH 11-13 (lysine-proline-valine) on fever in the rabbit,” Peptides, vol. 5, no. 4, pp. 815–817, Aug. 1984, doi: 10.1016/0196-9781(84)90027-5.
7. T. Brzoska, T. A. Luger, C. Maaser, C. Abels, and M. Böhm, “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., vol. 29, no. 5, pp. 581–602, Aug. 2008, doi: 10.1210/er.2007-0027.
8. T. A. Luger and T. Brzoska, “α‐MSH related peptides: a new class of anti‐inflammatory and immunomodulating drugs,” Ann. Rheum. Dis., vol. 66, no. Suppl 3, pp. iii52–iii55, Nov. 2007, doi: 10.1136/ard.2007.079780.
9. M. Cutuli, S. Cristiani, J. M. Lipton, and A. Catania, “Antimicrobial effects of alpha-MSH peptides,” J. Leukoc. Biol., vol. 67, no. 2, pp. 233–239, Feb. 2000, doi: 10.1002/jlb.67.2.233.
10. M. F. Masman et al., “Synthesis and conformational analysis of His-Phe-Arg-Trp-NH2 and analogues with antifungal properties,” Bioorg. Med. Chem., vol. 14, no. 22, pp. 7604–7614, Nov. 2006, doi: 10.1016/j.bmc.2006.07.007.
11. K. S. de Souza et al., “Improved cutaneous wound healing after intraperitoneal injection of alpha-melanocyte-stimulating hormone,” Exp. Dermatol., vol. 24, no. 3, pp. 198–203, Mar. 2015, doi: 10.1111/exd.12609.
12. C. Lonati et al., “Modulatory effects of NDP-MSH in the regenerating liver after partial hepatectomy in rats,” Peptides, vol. 50, pp. 145–152, Dec. 2013, doi: 10.1016/j.peptides.2013.10.014.
13. G. Colombo et al., “Gene expression profiling reveals multiple protective influences of the peptide alpha-melanocyte-stimulating hormone in experimental heart transplantation,” J. Immunol. Baltim. Md 1950, vol. 175, no. 5, pp. 3391–3401, Sep. 2005, doi: 10.4049/jimmunol.175.5.3391.
14. G. Colombo et al., “Production and effects of alpha-melanocyte-stimulating hormone during acute lung injury,” Shock Augusta Ga, vol. 27, no. 3, pp. 326–333, Mar. 2007, doi: 10.1097/01.shk.0000239764.80033.7e.
15. M. Schiller et al., “Human Dermal Fibroblasts Express Prohormone Convertases 1 and 2 and Produce Proopiomelanocortin-Derived Peptides,” J. Invest. Dermatol., vol. 117, no. 2, pp. 227–235, Aug. 2001, doi: 10.1046/j.0022-202x.2001.01412.x.
16. T. Brzoska, M. Böhm, A. Lügering, K. Loser, and T. A. Luger, “Terminal signal: anti-inflammatory effects of α-melanocyte-stimulating hormone related peptides beyond the pharmacophore,” Adv. Exp. Med. Biol., vol. 681, pp. 107–116, 2010, doi: 10.1007/978-1-4419-6354-3_8.
17. S. J. Getting, H. B. Schiöth, and M. Perretti, “Dissection of the anti-inflammatory effect of the core and C-terminal (KPV) alpha-melanocyte-stimulating hormone peptides,” J. Pharmacol. Exp. Ther., vol. 306, no. 2, pp. 631–637, Aug. 2003, doi: 10.1124/jpet.103.051623.
18. K. Pawar, C. S. Kolli, V. K. Rangari, and R. J. Babu, “Transdermal Iontophoretic Delivery of Lysine-Proline-Valine (KPV) Peptide Across Microporated Human Skin,” J. Pharm. Sci., vol. 106, no. 7, pp. 1814–1820, Jul. 2017, doi: 10.1016/j.xphs.2017.03.017.