Ampyrone (4-Aminoantipyrine) is a Direct Agonist of Human Tyrosinase and Potential Therapeutic for Oculocutaneous Albinism and Disorders of Hypopigmentation

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Abstract Significant loss of pigmentation can increase visual disability, skin cancer risk, and psychosocial stress. Tyrosinase (TYR) catalyzes the first and rate-limiting step of melanin synthesis. Inhibitors of TYR are well established and are currently used in clinical settings; however, there is a dearth of direct activators of TYR. Here, using a unique human TYR construct, high-throughput screening, and computational analysis techniques, we identified ampyrone as a TYR activator. Ampyrone increased the in vitro catalytic activity of the intramelanosomal domain of human TYR (hTYR) and its hypomorphic variant, P406L, a cause of oculocutaneous albinism type 1B (OCA1B). Moreover, ampyrone induced melanin synthesis in both wild-type and OCA1B human melanocytes, as well as 3-dimension (3D) human skin cultures. Our results reveal ampyrone as a lead compound for first-in-class TYR activators, potentially accelerating the discovery of novel therapies for patients with genetic and acquired diseases of hypopigmentation.

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