KPV Peptide – A Potent Anti-Inflammatory Agent
Human body consists of various endogenous peptide hormones that are vital for the key body functions and overall development and wellbeing. One such group of hormones is called melanocyte stimulating hormones or melanotropins. These hormones are primarily responsible for hair and skin pigmentation, maintain optimal energy levels in the body, play key role in sexual activity and help protect against inflammation.
Out of this class of melanotropin hormones, the most important hormones are alpha melanocyte stimulating hormones (a-MSH). a-MSH is an endogenous peptide hormone, composed of 13 amino acids, and is responsible for metabolic activities, sexual behavior and skin pigmentation.
Over time, with the help of continuous research on a-MSH hormones, scientists were able to isolate a fragment of this protein hormone and identify its biological effects, especially its anti-inflammatory properties. This fragment is known as KPV peptide.
KPV peptide is composed of three amino acids namely Lysine, Proline, and Valine (1).
This peptide is a C-terminal fragment of the a-MSH protein hormone, which is considered to be the primary amino acid sequence in the hormone that is responsible for its properties (2).
A study (2) was published in 1989 illustrating the reason why the tripeptide was isolated and how its biological effects were determined.
Upon discovering that the COOH terminal peptide in the a-MSH hormone is the primary amino acid messenger sequence, scientists conducted a preliminary research where it was seen that this tripeptide prevented excessive increase in vasopermeability. Excessive vasopermeability may lead to excess swelling of the blood vessels. This led to the belief that this COOH fragment may possess anti-inflammatory properties.
To confirm this concept, scientists isolated the tripeptide, namely KPV peptide and conducted a grading dose study (2) where the peptide was administered in mice in increased doses to determine its effects against swelling of the ears. After completion of study, it was seen that the isolated fragment inhibited the swelling in a dose dependent fashion. This confirmed that the endogenous tripeptide fraction possessed anti-inflammatory properties and more detailed studies should be conducted to fully explore this compound.
Peptide Working Mechanism
The peptide mainly exerts its anti-inflammatory effects by inactivating the inflammatory pathways. The peptide enters the cells or the cellular nuclei, directly interacts with the signaling molecules and prevents inflammation (3).
It can also inhibit the synthesis and release of the proinflammatory cytokine cells in the intestinal and immune cells. This also further helps reduce the swelling and inflammation in the body, suggesting that the compound may be beneficial in combating various diseases including colitis and inflammatory bowel disease (IBD).
Biological Effects of KPV
KPV peptide has demonstrated various advantages in the therapeutic field, including:
- Inhibits intestinal inflammation
- Use as an anti-inflammatory agent
- Possess antipyretic properties
- Helps in the healing of wounds
- Prevents formation of hypertrophic scars
- Increased body mass
- Does not cause skin pigmentation, as opposed to its originating molecule a-MSH hormone
Research and Clinical Studies
Intestinal Protection Studies
A study (4) was conducted on mouse models to determine the effects of the peptide on the intestinal inflammation.
The experiment was conducted on mice infected with inflammatory bowel disease (IBD). These experimental mice were divided into two groups, one was treated with the peptide whereas the other with the placebo.
After the treatment, the peptide treated mice showed robust results including reduced inflammatory cells and anti-enzymatic properties. The KPV induced mice showed faster recovery and significant weight gain, demonstrating that the compound has potent anti-inflammatory properties.
Another study (5) was conducted on the mouse model suffering from an inflamed intestine that was administered with tripeptide treated with a chemical called hyaluronic acid. This chemical induced compound was administered orally in the mice to aid targeted delivery of the peptide to specific locations in the intestine.
This experiment showed that the compound led to increased mucosal healing and improved anti-inflammatory effects. This result suggested that the peptide is highly potent, and mutating the compound leads to improved oral bioavailability.
Studies with Human Intestinal Cells
This study (6) was conducted on the cell culture comprised of inflamed human intestinal cells. The main purpose of this study was to determine the effects and mechanism of the compound against inflammation.
In humans, there is an endogenous transporter namely PepT1 present in the small intestine, and is stimulated under conditions such as inflammatory bowel disease (IBD). Human intestinal cells from such IBD candidates were isolated and treated with either KPV or placebo.
Upon treatment, these cells were examined and results showed that even small nanomolar concentrations of the peptide led to anti-inflammatory effects by inhibiting inflammatory signals. KPV peptide mainly acted via PepT1 expression in these intestinal cells, suggesting that PepT1 plays a role in transporting the peptide to the affected site and once at the site, it would then exert its anti-inflammatory effects.
This outcome suggested that the peptide may be a potential candidate in treating IBD ailments in patients.
Studies Demonstrating Antipyretic Properties
Previous studies conducted showed that a-MSH hormone tridecapeptide helped reduce fever when given in small doses. Since the a-MSH 1-10 amino acid sequence showed no antipyretic (i.e. fever reducing) properties, it was indicative that the tripeptide compound 11-13 was critical to combat fevers.
In a 1984 study (7), rabbits were administered with the peptide via an intravenous route of administration, to examine its effects on the nervous system, at doses of 0.5 to 2.0 mg per body weight. After the administration, it was seen that all the doses from 0.5 to 2.0 mg showed excellent antipyretic properties reducing the body temperature to optimal levels.
Research has shown that the intact a-MSH has several added advantages besides combating fever such as treating dermatitis, arthritis, and inflammation of the eyes, lungs and gastrointestinal tract. However, the main side effect of the intact molecule was that it caused skin pigmentation. KPV peptide, on the other hand, does not cause this side effect – which is an added advantage of the compound over the intact molecule (8).
Swelling of the Ears Studies
A comparative study analysis (9) was conducted to demonstrate the effects of a-MSH and KPV on the swelling (inflammation) of the organs.
An experiment was conducted on the mice suffering from swollen ears due to skin rashes and dermatitis. The mice were divided in two groups – one was treated with irritant (to induce ear swelling) and peptide, and the other with the irritant and a-MSH molecule.
After 24 hours, both groups showed an equal improvement in reducing the swelling of ears. However, after 2 weeks, when the compound administration was stopped and only the irritant was administered, the results showed a-MSH treated mice had more reduced swelling compared to the other group.
This suggested that the peptide was potent in inhibiting the swelling of ears. While the effects were not as long lasting as was in the case of a-MSH molecule, the results indicate that the continuous administration of the peptide may lead to better and longer effects.
Wound Healing Effects of KPV
Wound healing is a complex biological process comprised of three general phases namely – inflammation, proliferation and remodeling of the skin, tissue, or cells. This process is characterized by different types of cells and concentrations of cytokines in the wounded area.
Though every wound and associated cells affected by the wound may differ, most of the cells possess a receptor called melanocortin 1 receptor (MC1R). This receptor is where the a-MSH hormone binds, indicating that hormone analogues such as KPV peptide can also bind to these receptors (10).
Advantages of KPV over a-MSH and other anti-inflammatory medications:
Typically, when a-MSH binds with these receptors and produces wound healing effects, it also usually causes darkening of the skin and scar formation upon healing. In case of the peptide, this pigmentation of the skin and subsequent darkening and scar development can be avoided. This fact is the main added advantage of the peptide over the endogenous hormone.
The other benefit to note is that, based on the research conducted (11), the peptide possesses antimicrobial properties, mainly against Staphylococcus aureus and Candida albicans. This suggests that the peptide compound is equally effective in obstructing skin infections which usually occur after serious wounds and burns. This is in contrast to most of the anti-inflammatory medications which in fact lower the body’s mechanism to fight against such infections.
Chronic Scar Formation
Besides the first phase (inflammation) of wound healing, KPV is also known to play a role in the other two phases (proliferation and remodeling) of the process. Chronic scar formation mainly occurs due to excessive infiltration of the macrophagic cells, increased levels of neutrophils and spiked immunoreactivity.
A study (12) was conducted to further understand the effects of peptide on scar recovery. Young mice were administered with either 1 mg/kg body weight of peptide or control via intraperitoneal route of administration. Half an hour later, these mice were subjected to two 6.5 mm wide hole formation on their dorsal skin, under anesthesia. The wound healing and scar formation effects were then analyzed on days 3, 7, 40, and 60.
On days 3 and 7, it was noted that the peptide treated mice showed improved healing on the skin due to reduced levels of inflammatory cells such as leukocytes and mast cells. On days 40 and 60, it was observed that the peptide treated mice had a lesser scar area than the vehicle group.
This outcome suggested that not only is the peptide effective in preventing scar formation on skin, but can also be used to treat wounds on other tissues such as the heart and lungs. Certain chemotherapeutic treatments lead to scarring of tissues, and there’s hope that the peptide, when used as an adjunct with anti-cancer treatments, can prevent such scar formation and result in better reactions.
Clinical trials with KPV are yet to be conducted to fully demonstrate the potential of the peptide in the human body.
However, as with other peptides, some common side effects may include:
- Pain, redness, and itchiness at the site of peptide injection
- Overdose may lead to water retention and swelling
- Dry mouth
- High blood pressure
- Pain in joints
- Weight gain
KPV versus a-MSH
Continuous research between the two compounds have shown that while the peptide is an analogue of the hormone, there are certain differences between the two, which should be taken into consideration depending on the intended use:
a-MSH, the intact molecule, is the more potent molecule amongst the two. However, it has a serious drawback – excessive skin pigmentation – which is not seen in the case of the peptide. Furthermore, the peptide is remarkably easy to manufacture, thus making it less costly than the other compound (13).
a-MSH exerts its anti-inflammatory effects by binding with melanocortin receptors, including MC3 and MC4 receptors. The peptide does not bind to these MC3/4 receptors, but only to specific melanocortin receptors (such as MC1R). Thus, the mechanism of action of the two also differs (14).
Lastly, the peptide is more versatile in terms of administration – it can be easily administered via injections (either centrally or peripherally) through subcutaneous and intraperitoneal route, and can also be given orally. Latest research (15) also shows that the peptide may be administered transdermally. This vast range of administrations suggest that the peptide will be more convenient for the patients to intake in the future.
KPV peptide is an analogue fraction of the naturally occurring a-MSH hormone peptide, composed of three amino acids. Similar to its parent molecule, the peptide possesses potent anti-inflammatory properties, in addition to other biological effects such as wound healing and scar recovery.
The peptide exerts its properties mainly by binding with the MC1R receptors and preventing the inflammatory signaling pathways in the cells. In human intestines, the peptide functions via PepT1 mediated pathway and obstructs the formation and secretion of the inflammatory molecules such as leukocytes. Studies so far have demonstrated that the peptide is highly potent and may be used as a therapeutic agent to combat IBD, colitis, burns and also potentially be used as an adjunct with anti-cancer treatments.
Continued research and clinical trials are being conducted to fully explore the peptide characteristics to determine its potential as a therapeutic agent to treat human ailments.
(1) Dalmasso, G., Charrier-Hisamuddin, L., Nguyen, H. T., Yan, Y., Sitaraman, S., & Merlin, D. (2008). PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation. Gastroenterology, 134(1), 166–178. https://doi.org/10.1053/j.gastro.2007.10.026
(2) Hiltz ME, Lipton JM. Antiinflammatory activity of a COOH-terminal fragment of the neuropeptide alpha-MSH. FASEB J. 1989 Sep;3(11):2282-4. https://pubmed.ncbi.nlm.nih.gov/2550304/
(3) 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 Aug;29(5):581-602. doi: 10.1210/er.2007-0027. Epub 2008 Jul 8. https://pubmed.ncbi.nlm.nih.gov/18612139/
(4) Klaus Kannengiesser, MD, Christian Maaser, MD, Jan Heidemann, MD, Andreas Luegering, MD, Matthias Ross, MD, Thomas Brzoska, PhD, Markus Bohm, MD, Thomas A. Luger, MD, Wolfram Domschke, MD, Torsten Kucharzik, MD, Melanocortin-derived tripeptide KPV has anti-inflammatory potential in murine models of inflammatory bowel disease, Inflammatory Bowel Diseases, Volume 14, Issue 3, 1 March 2008, Pages 324–331, https://doi.org/10.1002/ibd.20334
(5) Klaus Kannengiesser, MD, Christian Maaser, MD, Jan Heidemann, MD, Andreas Luegering, MD, Matthias Ross, MD, Thomas Brzoska, PhD, Markus Bohm, MD, Thomas A. Luger, MD, Wolfram Domschke, MD, Torsten Kucharzik, MD, Melanocortin-derived tripeptide KPV has anti-inflammatory potential in murine models of inflammatory bowel disease, Inflammatory Bowel Diseases, Volume 14, Issue 3, 1 March 2008, Pages 324–331. https://pubmed.ncbi.nlm.nih.gov/28143741/
(6) Dalmasso G, Charrier-Hisamuddin L, Nguyen HT, Yan Y, Sitaraman S, Merlin D. PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation. Gastroenterology. 2008 Jan;134(1):166-78. https://pubmed.ncbi.nlm.nih.gov/18061177/
(7) D.B. Richards, J.M. Lipton, Effect of α-MSH 11–13 (lysine-proline-valine) on fever in the rabbit, Peptides, Volume 5, Issue 4, 1984, Pages 815-817, ISSN 0196-9781, https://doi.org/10.1016/0196-9781(84)90027-5.
(8) Luger TA, Brzoska T. alpha-MSH related peptides: a new class of anti-inflammatory and immunomodulating drugs. Ann Rheum Dis. 2007 Nov;66 Suppl 3(Suppl 3):iii52-5. https://pubmed.ncbi.nlm.nih.gov/17934097/
(9) Luger, T. A., & Brzoska, T. (2007). alpha-MSH related peptides: a new class of anti-inflammatory and immunomodulating drugs. Annals of the rheumatic diseases, 66 Suppl 3(Suppl 3), iii52–iii55. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2095288/#!po=3.33333
(10) 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 Aug;29(5):581-602. https://pubmed.ncbi.nlm.nih.gov/18612139/
(11) Cutuli M, Cristiani S, Lipton JM, Catania A. Antimicrobial effects of alpha-MSH peptides. J Leukoc Biol. 2000 Feb;67(2):233-9. doi: 10.1002/jlb.67.2.233. PMID: 10670585. https://pubmed.ncbi.nlm.nih.gov/10670585/
(12) de Souza KS, Cantaruti TA, Azevedo GM Jr, Galdino DA, Rodrigues CM, Costa RA, Vaz NM, Carvalho CR. Improved cutaneous wound healing after intraperitoneal injection of alpha-melanocyte-stimulating hormone. Exp Dermatol. 2015 Mar;24(3):198-203. https://pubmed.ncbi.nlm.nih.gov/25431356/
(13) Brzoska T, Böhm M, Lügering A, Loser K, Luger TA. Terminal signal: anti-inflammatory effects of α-melanocyte-stimulating hormone related peptides beyond the pharmacophore. Adv Exp Med Biol. 2010;681:107-16. https://pubmed.ncbi.nlm.nih.gov/21222263/
(14) Stephen Gettin et al, Dissection of the Anti-Inflammatory Effect of the Core and C-Terminal (KPV) -Melanocyte-Stimulating Hormone Peptides, Journal of Pharmacology and Experimental Therapeutics, September 2003. http://dx.doi.org/10.1124/jpet.103.051623
(15) Pawar K, Kolli CS, Rangari VK, Babu RJ. Transdermal Iontophoretic Delivery of Lysine-Proline-Valine (KPV) Peptide Across Microporated Human Skin. J Pharm Sci. 2017 Jul;106(7):1814-1820. https://pubmed.ncbi.nlm.nih.gov/28343991/
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