Afamelanotide - Mechanism of Action

Mechanism of Action

Afamelanotide is a selective agonist of the melanocortin 1 receptor (MC₁R). As an analogue of α-MSH, its mechanism of action is biomimicry of the natural mammalian tanning process.

Afamelanotide produces its photoprotective effects by triggering a 'signaling cascade' via its activation of the MC₁R on melanin-producing cells known as melanocytes.

Upon afamelanotide binding with the MC₁R on the surface of melanocytes in the epidermal layer of the skin, it begins a series of actions and reactions that result in melanocytes favoring the production of eumelanin (photoprotective black/brown pigment) over pheomelanin (red/yellow pigment).

The initial binding activates the MC₁R leading to the activation of adenylate cyclase (AC) and stimulation of the production of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). cAMP in turn activates protein kinase A (PKA) resulting in the phosphorylation of the cAMP response element-binding (CREB). Phosphorylated CREB will bind to the cAMP response element (CRE) on the microphthalmia-associated transcription factor (MITF) gene leading to the synthesis of the MITF protein. MITF has the ability to activate several genes by binding to them, including the MC₁R gene and the genes involved in melanogenesis (tyrosinase, TYRP1 and DCT, which encode enzymes of the same names). This results in increased concentrations of the melanogenic enzymes within the melanocyte. It is the levels of these enzymes within a melanocyte that determines whether the cell will create eumelanin instead of pheomelanin.

Production of eumelanin rather than pheomelanin by melanocytes, thereby increases pigmentation of the skin and thus provides photoprotection against harmful UV radiation from the sun. This is the intended therapeutic benefit from the medicinal administration of afamelanotide.