Identification and structural insight of an effective PPAR? modulator with improved therapeutic index for anti-diabetic drug discovery.

ABSTRACT: Peroxisome proliferator-activated receptor ? (PPAR?) is a key regulator of glucose homeostasis and lipid metabolism, and an important target for the development of modern anti-diabetic drugs. However, current PPAR?-targeting anti-diabetic drugs such as classical thiazolidinediones (TZDs) are associated with undesirable side effects. To address this concern, we here describe the structure-based design, synthesis, identification and detailed in vitro and in vivo characterization of a novel, decanoic acid (DA)-based and selective PPAR? modulator (SPPAR?M), VSP-77, especially (S)-VSP-77, as the potential "hit" for the development of improved and safer anti-diabetic therapeutics. We have also determined the co-crystal structure of the PPAR? ligand-binding domain (LBD) in complex with two molecules of (S)-VSP-77, which reveal a previously undisclosed allosteric binding mode. Overall, these findings not only demonstrate the therapeutic advantage of (S)-VSP-77 over current TZD drugs and representative partial agonist INT131, but also provide a rational basis for the development of future SPPAR?Ms as safe and highly efficacious anti-diabetic drugs.

SUBMITTER: Jiang H 

PROVIDER: S-EPMC7059199 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature