Visual fluorescence discovery of the potent photoswitchable hTYR inhibitor to improve treatment strategy for hyperpigmentation

Abstract

Hyperpigmentation, which is caused by excess melanin production by melanocytes with human tyrosinase (hTYR) playing a pivotal role, can lead to various dermatological disorders. Therefore, the discovery and utilization of novel human tyrosinase inhibitors represent a promising therapeutic strategy. Herein, a new fluorescent probe THT-1 was developed for the first time to recognize human tyrosinase instead of mushroom tyrosinase based on the thalidomide fluorescent skeleton. This green probe can not only screen for novel photoswitchable indole-2-ketone-based human tyrosinase inhibitors with better visual sensitivity, but also effectively recognize endogenous tyrosinase at both cellular and zebrafish levels. By meticulously monitoring fluorescence intensity variations, the impact of photoswitchable inhibitors on tyrosinase activity has been tracked, both in vitro and in vivo. These results demonstrate that a multifunctional thalidomide-based probe has been successfully obtained, which facilitates the identification of potent photoswitchable human tyrosinase inhibitors. Moreover, a potent photoswitchable tyrosinase inhibitor T-1 for reducing melanin levels in A375 cells and zebrafish has been also successfully developed, thus potentially advancing new treatment approaches for hyperpigmentation.