Melanotan I

Melanotan I (afamelanotide, brand name Scenesse) is a synthetic analog of alpha-melanocyte-stimulating hormone (α-MSH), an endogenous peptide that regulates skin pigmentation and photoprotection. It is the first melanocortin peptide to receive regulatory approval: the European Medicines Agency (EMA) approved it in 2014, and the FDA approved it in October 2019 for the prevention of phototoxicity in adults with erythropoietic protoporphyria (EPP).

EPP is a rare inherited metabolic disorder caused by mutations in the ferrochelatase (FECH) gene, resulting in accumulation of protoporphyrin IX in red blood cells, plasma, and skin. Exposure to visible light triggers a severe, painful phototoxic reaction in affected individuals, restricting sun exposure and severely limiting quality of life. Afamelanotide addresses this by constitutively inducing eumelanin production independent of UV exposure, raising the photosensitivity threshold.

Melanotan I is structurally distinct from Melanotan II (PT-141 analog) and has a different receptor profile and approved indication. The two should not be confused.

Afamelanotide is a superpotent, long-acting MC1R (melanocortin-1 receptor) agonist. Two amino acid substitutions distinguish it from native α-MSH: - **Position 4:** Methionine → Norleucine (Nle) — increases metabolic stability, eliminates oxidation liability - **Position 7:** Phe → D-Phe — resists proteolytic degradation, dramatically increases receptor affinity (~1000-fold potency increase over native α-MSH)

Upon MC1R binding, afamelanotide activates adenylyl cyclase via Gαs → cAMP elevation → PKA activation → phosphorylation of MITF (microphthalmia-associated transcription factor). MITF upregulates tyrosinase and related enzymes (TYRP1, DCT) in melanocytes, switching melanogenesis from pheomelanin (UV-sensitizing) to eumelanin (UV-absorbing, free radical-scavenging).

Eumelanin acts as a natural sunscreen, increasing the minimum erythemal dose and attenuating the protoporphyrin IX-mediated phototoxic cascade in EPP. Because afamelanotide activates this pathway constitutively — without requiring UV stimulus — it provides photoprotection even before sun exposure.