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

Obesity stands as a global epidemic and is 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 can also assist in sustained weight loss. Here, we report the design of a new generation of prohibitin peptide-based therapeutics engineered to target white adipose tissues. These peptides demonstrate significant reduction of body weight in a high-fat diet-induced obesity mouse model and represent a paradigm shift in approaches to the treatment of obesity by inducing mitochondrial uncoupling. The most potent compound, PTP-r, was prohibitin-TP01 substituted with d-arginine. Overall, the study reveals the promising development of next-generation adipose-targeting prohibitin peptides, capable of curbing adipocyte expansion and body weight, with favorable preclinical safety profiles. These peptides hold immense potential for developing new treatments to address obesity and metabolic syndrome.