Melanocortin Explained

The melanocortins are a family of neuropeptide hormones which are the ligands of the melanocortin receptors.[1] The melanocortin system consists of melanocortin receptors, ligands, and accessory proteins. The genes of the melanocortin system are found in chordates.[2] Melanocortins were originally named so because their earliest known function was in melanogenesis. It is now known that the melanocortin system regulates diverse functions throughout the body, including inflammatory response, fibrosis, melanogenesis, steroidogenesis, energy homeostasis, sexual function, and exocrine gland function.[3] [4]

There are four endogenous melanocortin agonists which are derived from post-transcriptional processing of the precursor molecule proopiomelanocortin (POMC) (Figure 1).[5] They are Adrenocorticotropic hormone (ACTH), a-melanocyte stimulating hormone (MSH), b-MSH, and g-MSH. In addition to agonists which activate melanocortin receptors, there are two antagonists which inhibit receptor activity, Agouti and Agouti-related protein (Agrp). Lastly, the ligand β-defensin 3 acts as a neutral melanocortin receptor antagonist.[6]

Receptors

The 5 melanocortin receptors are seven-transmembrane G-protein coupled receptors with differing ligand affinities, tissue and cell type expression, and downstream functions (Figure 2).[7] MC1R is expressed on melanocytes, macrophages, epithelial cells, endothelial cells, fibroblasts, monocytes and numerous other immune cells, but is also present in brain, testis, and intestine.[8] Its main functions are in melanogenesis and anti-inflammatory signaling.[9] MC2R is expressed in the adrenal cortex and adipocytes and promotes steroidogenesis.[10] MC3R and MC4R are primarily expressed in the brain and regulate energy homeostasis. MC3R is additionally involved in immunomodulation while MC4R has a role in sexual function.[11] [12] MC5R is highly expressed in skin and adrenal glands and has a role in exocrine function.[13] MC2R is activated exclusively by ACTH, whereas the other 4 receptors can be activated by ACTH, a-MSH, b-MSH, and g-MSH, although the binding affinities differ. For all the melanocortin receptors, binding of an agonistic ligand activates the receptor, leading to dissociation of the G protein and activation of the enzyme adenyl cyclase. Adenyl cyclase then cleaves ATP to generate the second messenger cyclic AMP (cAMP), which in turn activates multiple downstream pathways.  

There are two known accessory proteins belonging to the melanocortin system which modulate function of the receptors. These are melanocortin-2-receptor accessory protein (MRAP) and MRAP2.[14]

Therapeutic Uses

FDA-approved

In 2019 the FDA approved the first drug targeting melanocortin receptors, Vyleesi (Bremelanotide) which was developed by Palatin Technologies, Inc.  The Melanocortin system has been largely unexplored in drug development but recent approvals, its novelty and wide-spread application across indications has led it to the frontier of new discoveries in medicine. Since Vyleesi approval  multiple companies have initiated drug discovery programs targeting the melanocortin system. Bremelanotide (Vyleesi) is approved for treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women.[15] At therapeutic dose levels, it activates MC1R and MC4R.[16]

Setmelanotide (Imcivree) is an MC4R agonist approved for chronic weight management in patients with genetic obesity.[17] [18]

Afamelanotide (Scenesse) is an MC1R agonist approved for patients with erythropoietic protoporphyria to increase pain-free light exposure.[19]

Clinical trials

PL9643, an ophthalmic solution, is being tested in phase 3 clinical trials to determine safety and efficacy in patients with dry eye.[20] PL9643 activates MC1R, MC3R, MC4R and MC5R. Completed Phase 2 studies demonstrated positive results for the treatment of dry eye disease.[21]

Dersimelagon (MT-7117) is an orally administered MC1R agonist being tested in phase 3 clinical trials to evaluate safety and tolerability in patients with erythropoietic protoporphyria or X-linked protoporphyria.[22]

Resomelagon (AP1189) is an orally administered MC1R and MC3R agonist being tested in three phase 2 clinical trials to study safety and efficacy in patients with rheumatoid arthritis and idiopathic membranous nephropathy.[23] [24] [25]

Function

The melanocortin system is one of the mammalian body's tools to regulate food intake in a push-pull fashion.[26] The only neurons known to release melanocortins are located in the arcuate nucleus of the hypothalamus. However, melanocortins are also produced by keratinocytes in response to UV exposure. Accordingly, there is a subpopulation called POMC neurons and one called AgRP neurons. When POMC neurons release α-MSH, appetite is decreased. On the other hand, when AgRP neurons release AgRP, appetite is stimulated.

Leptin, the energy surfeit hormone, and Ghrelin, the hunger hormone, are upstream regulators of the melanocortin system in the brain.[27] These hormones also regulate the release of peptides other than the melanocortins. Disturbance of the leptin-melanocortin pathway can lead to early onset obesity as well as various metabolic disorders and suppressed immune function. [28]

Notes and References

  1. Ericson, M.D., et al., Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016. Biochim Biophys Acta Mol Basis Dis, 2017. 1863(10 Pt A): p. 2414-2435.
  2. Cortes, R., et al., Evolution of the melanocortin system. Gen Comp Endocrinol, 2014. 209: p. 3-10.
  3. Chen, W., et al., Exocrine gland dysfunction in MC5-R-deficient mice: evidence for coordinated regulation of exocrine gland function by melanocortin peptides. Cell, 1997. 91(6): p. 789-98.
  4. Wang, W., et al., Melanocortin Regulation of Inflammation. Front Endocrinol (Lausanne), 2019. 10: p. 683.
  5. Arnason, B.G., et al., Mechanisms of action of adrenocorticotropic hormone and other melanocortins relevant to the clinical management of patients with multiple sclerosis. Mult Scler, 2013. 19(2): p. 130-6.
  6. Nix, M.A., et al., Molecular and functional analysis of human beta-defensin 3 action at melanocortin receptors. Chem Biol, 2013. 20(6): p. 784-95.
  7. Butler, A.A., et al., A Life without Hunger: The Ups (and Downs) to Modulating Melanocortin-3 Receptor Signaling. Front Neurosci, 2017. 11: p. 128.
  8. Salazar-Onfray, F., et al., Tissue distribution and differential expression of melanocortin 1 receptor, a malignant melanoma marker. Br J Cancer, 2002. 87(4): p. 414-22.
  9. Wolf Horrell, E.M., M.C. Boulanger, and J.A. D'Orazio, Melanocortin 1 Receptor: Structure, Function, and Regulation. Front Genet, 2016. 7: p. 95.
  10. Fridmanis, D., A. Roga, and J. Klovins, ACTH Receptor (MC2R) Specificity: What Do We Know About Underlying Molecular Mechanisms? Front Endocrinol (Lausanne), 2017. 8: p. 13.
  11. Catania, A., et al., Targeting melanocortin receptors as a novel strategy to control inflammation. Pharmacol Rev, 2004. 56(1): p. 1-29.
  12. Martin, W.J. and D.E. MacIntyre, Melanocortin receptors and erectile function. Eur Urol, 2004. 45(6): p. 706-13.
  13. Hatta, N., et al., Expression, candidate gene, and population studies of the melanocortin 5 receptor. J Invest Dermatol, 2001. 116(4): p. 564-70.
  14. Chan, L.F., et al., MRAP and MRAP2 are bidirectional regulators of the melanocortin receptor family. Proc Natl Acad Sci U S A, 2009. 106(15): p. 6146-51.
  15. Administration, U.F.a.D. FDA approves new treatment for hypoactive sexual desire disorder in premenopausal women. 2019; Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-hypoactive-sexual-desire-disorder-premenopausal-women#:~:text=FDA%20approves%20new%20treatment%20for%20hypoactive%20sexual%20desire%20disorder%20in%20premenopausal%20women,-Share&text=The%20U.S.%20Food%20and%20Drug,(HSDD)%20in%20premenopausal%20women.
  16. Administration, U.F.a.D. Vyleesi prescribing information. 2019; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210557s000lbl.pdf.
  17. Administration, U.F.a.D. FDA approves first treatment for weight management for people with certain rare genetic conditions. 2020; Available from: https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-weight-management-people-certain-rare-genetic-conditions#:~:text=%5B11%2F27%2F2020%5D,POMC)%20deficiency%2C%20proprotein%20subtilisin%2F.
  18. Markham, A., Setmelanotide: First Approval. Drugs, 2021. 81(3): p. 397-403.
  19. Administration, U.F.a.D. FDA approves first treatment to increase pain-free light exposure in patients with a rare disorder. 2019; Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-increase-pain-free-light-exposure-patients-rare-disorder.
  20. Administration, U.F.a.D. A Phase 3, Multi-Center Study Evaluating PL9643 in Patients With Dry Eye (MELODY-1). 2022; Available from: https://clinicaltrials.gov/ct2/show/NCT05201170?term=palatin&draw=2&rank=1.
  21. Administration, U.F.a.D. Efficacy and Safety of PL9643 Ophthalmic Solution in Subjects With Dry Eye. 2020; Available from: https://clinicaltrials.gov/ct2/show/NCT04268069?term=palatin&draw=2&rank=9.
  22. Administration, U.F.a.D. Extension Study to Evaluate Safety and Tolerability of Oral Dersimelagon (MT-7117) in Subjects With Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP). 2021; Available from: https://clinicaltrials.gov/ct2/show/NCT05005975?term=mt-7117&draw=2&rank=9.
  23. Administration, U.F.a.D. A Study of the Safety, Tolerability, Pharmacokinetics and Efficacy of Treatment With AP1189 in Patients With iMN. 2020; Available from: https://clinicaltrials.gov/ct2/show/NCT04456816?term=ap1189&draw=2&rank=2.
  24. Administration, U.F.a.D. A Safety & Efficacy Study of Treatment With AP1189 in Rheumatoid Arthritis Patients naïve to DMARD Treatment (EXPAND); Available from: https://clinicaltrials.gov/ct2/show/NCT05516979
  25. Administration, U.F.a.D. A Dose-range Study of the Safety and Efficacy of Treatment in Adult Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate (RESOLVE); Available from: https://clinicaltrials.gov/ct2/show/NCT05604885
  26. Zhou Y, Rui L . Leptin signaling and leptin resistance . Frontiers of Medicine . 7 . 2 . 207–22 . June 2013 . 23580174 . 4069066 . 10.1007/s11684-013-0263-5 .
  27. Klok MD, Jakobsdottir S, Drent ML . The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review . Obesity Reviews . 8 . 1 . 21–34 . January 2007 . 17212793 . 10.1111/j.1467-789x.2006.00270.x . 24266123 . free .
  28. Nunziata A, Borck G, Funcke JB, Kohlsdorf K, Brandt S, Hinney A, Moepps B, Gierschik P, Debatin KM, Fischer-Posovszky P, Wabitsch M . Estimated prevalence of potentially damaging variants in the leptin gene . Molecular and Cellular Pediatrics . 4 . 1 . 10 . November 2017 . 29101506 . 5670095 . 10.1186/s40348-017-0074-x . free .

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