Mixed-Chirality Prohibitin Peptide: D-(RLARLAR)2 Enhances Stability and In Vivo Effects on Obesity

Obesity is a global epidemic and the primary risk factor for type 2 diabetes, ranking as the fifth leading cause of death worldwide. While lifestyle changes can address body fat accumulation, pharmacotherapies are essential for sustained weight loss. In this study, we report the design of a new generation of cationic-rich peptide-based therapeutics engineered to target white adipose tissues. Our findings demonstrate remarkable efficacy in significantly reducing body weight in a high-fat diet-induced mouse model. Notably, a prohibitin peptide substituted with D-arginine represents a paradigm shift by inducing mitochondrial uncoupling. This study heralds a promising avenue for developing the next generation of prohibitin-targeting peptides, capable of curbing adipocyte expansion and body weight, with favorable preclinical safety profiles. Altogether, these peptides hold immense potential for addressing obesity and metabolic syndrome.