296-LB: Novel Analogs of the Mitochondrially Encoded Peptide CB5064 Improve Body Weight and Glucose Tolerance in Dio Mice, and Demonstrate Selective Agonism at the Apelin Receptor

Abstract

Metabolic dysregulation is integral to the development and pathogenesis of many age-related diseases, including type 2 diabetes and obesity. Several mitochondrially encoded peptides have previously been shown to be secreted from cells and to act as regulatory signals for metabolic homeostasis, including MOTS-c, SHLP2, and humanin. Novel modified analogs of a newly identified mitochondrially encoded peptide, CB5064, have been synthesized and evaluated for plasma stability, activity in a broad screen of G protein-coupled receptor (GPCR) target engagement, and for potential biological activity in diet-induced obese (DIO) mice. In vitro evaluation demonstrated that CB5064 analogs interact with and activate the apelin receptor (APJ/AGTRL1/APLNR). The observed EC50 values of several novel CB5064 analogs at the apelin receptor were in the low µM range, in some cases achieving maximum responses similar to the natural substrate, Apelin-13. In DIO mice, once daily administration of the same series of CB5064 analogs demonstrated a range of effects on metabolic regulation, including significant reduction in body weight, selective fat mass loss, and improved glucose tolerance. The apelin receptor is widely expressed in tissues and appears to play a critical role in energy metabolism, cardiovascular function, fluid homeostasis, angiogenesis, and in diabetic complications. These mitochondria-based peptide analogs therefore represent an entirely new class of molecules with agonist activity at the apelin receptor and potential for use as a source of novel therapeutics for type 2 diabetes, cardiovascular disease, and other age-related disorders. Additional evaluation of the therapeutic potential of these peptides is ongoing. Disclosure K. Grindstaff: Employee; Self; CohBar, Inc. E. Stenger: None. R. Shang: Other Relationship; Self; CohBar Inc. T. Yu: None. W.C. Luo: None. V.V. Kim: None. D. Perez-Tilve: Research Support; Self; CohBar, Inc., Novo Nordisk A/S. K.C. Cundy: Employee; Self; CohBar, Inc. Stock/Shareholder; Self; CohBar, Inc.