The small molecule peroxiredoxin mimetics restore growth factor signalings and reverse vascular remodeling

Abstract

Epidithio-diketopiperazine (ETP) compound is the family of natural fungal metabolites that are known to exert diverse biological effects, such as immunosuppression and anti-cancer activity, in higher animals. However, an enzyme-like catalytic activity or function of the ETP derivatives has not been reported. Here, we report the generation of novel thiol peroxidase mimetics that possess peroxide-reducing activity through strategic derivatization of the core ETP ring structure. The ETP derivatives with small side chains are the bona fide 2-Cys peroxiredoxin (PRX) mimetics that catalyze the H2O2-reducing reaction specifically coupled to the thioredoxin/thioredoxin reductase system. In contrast, the ETP derivatives with linear chains or a heterocyclic group show H2O2-reducing activity in coupling with both thioredoxin and glutathione systems. Moreover, the ETP derivatives with bulky heterocyclic groups almost lose catalytic activity. The 2-Cys PRX mimetics regulate intracellular H2O2 levels, thereby restoring the receptor Tyr kinase signaling and cellular functions disrupted by the absence of 2-Cys PRX in vascular cells. In a rodent model, the 2-Cys PRX mimetics reverse vascular occlusion in the injured carotid arteries by inhibiting smooth muscle hyperplasia and promoting reendothelialization. Thus, this study reveals a novel chemical platform for complementing defective 2-Cys PRX enzymes in biological systems. © 2025 Elsevier Inc.