Colon-Targeting Supersulfide Donor-Drug Conjugates Align Forces against Inflammation

Supersulfides are rising stars in regulating redox. Their distinctive redox biological functions are becoming increasingly evident with the advancement of supersulfide donors. However, most existing donors are limited to releasing hydropersulfide (RSSH) only, and in addition, there is still a knowledge gap in translating supersulfides into therapeutic molecules. To this end, in this work, we devised and synthesized a supersulfide donor-drug conjugate, RSSS-ASA, containing an azo moiety. This bifunctional prodrug enables the production of hydrotrisulfide (RSSSH) catalyzed by intestinal azoreductase, accompanied by the release of the anti-inflammatory molecule 5-aminosalicylic acid (ASA). Notably, the corelease of the supersulfides with ASA exhibited colonic-targeting attributes, thereby synergistically contributing to the potent anti-inflammatory and antioxidant activities observed in cellular and animal models. This prodrug design is worthy of further development and translation in donor development and disease treatment.