CLINUVEL’s pharmaceutical development to date has focused on melanocortins, a group of small protein hormones that develop from the gene product proopiomelanocortin (POMC).
These hormones modulate physiological activity in the body by binding with specific melanocortin receptors, of which there are currently five identified: MC1R—MC5R. These receptors are widespread within the human body and present in virtually every organ, making the effects of the melanocortins widespread and varied.
Known physiological activity influenced by melanocortins includes pigmentation, inflammation, energy homeostasis, appetite and sexual function. Melanocortins expressed in the brain, or those which cross the blood-brain barrier and bind with MC3R and MC4R (the third and fourth melanocortin receptors), are thought to play a fundamental role in feeding and body weight. Melanocortin hormones are also expressed in peripheral tissues including the duodenum, kidneys, liver, ovaries, placenta, skin and testes, where they can have a more localised response.
Melanocortin receptors identified throughout the body
Alpha-melanocyte stimulating hormone (α-MSH) is a protein hormone produced in the body. It is part of a family of peptides known as melanocortins, all of which are cleaved from the precursor polypeptide proopiomelanocortin (POMC) and bind to specific melanocortin receptors throughout the body. α-MSH consists of 13 amino acids, with the sequence Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val.
Of the five known melanocortin receptors, α-MSH binds with various affinities to MC1R, MC3R, MC4R and MC5R. When bound to each of these receptors it is believed to have roles in: regulating pigmentation and inflammation, DNA repair, energy homeostasis, sexual behaviour, appetite regulation and exocrine function.
Alpha-melanocyte stimulating hormone in the skin
It is α-MSH’s role In stimulating melanin production (melanogenesis) in the skin which is arguably best understood. In the skin, α-MSH is produced by epidermal skin cells (keratinocytes and, less commonly, melanocytes and Langerhans cells) as a protective response to damage caused by ultraviolet radiation (UVR).
Alpha-MSH molecules then bind with the MC1R on melanocytes (pigment producing cells) to activate the synthesis of black-brown melanin, called eumelanin. Following this process, eumelanin granules are synthesised within intracellular packages called melanosomes which are then transported to the ends of tentacle-like projections in the cell, called dendrites.
The tips of these dendrites touch and release melanosomes into adjacent keratinocytes. The melanosomes cluster around keratinocyte nuclei to form a pigmented, protective barrier. The eumelanin within melanosomes shields cells from further UVR damage by absorbing, reflecting and refracting light.
In addition to activating melanin, α-MSH is known to have several other roles in the skin, although the exact mechanisms are not fully understood. Recent research has shown that α-MSH enhances the repair of DNA damage, a process known as nucleotide excision repair (NER), and reduces the generation of free radicals following UVR exposure. Both factors reduce the overall damage caused by UVR, thus reducing the risk factors for certain skin cancers. However some people with fairer skin types have reduced MC1R activity, meaning the response when α-MSH binds to the MC1R is impaired or absent. Alpha-MSH is also known to play a role in inhibiting both the expression and activity of inflammatory cytokines in the skin.