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

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Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) is a key regulator of glucose homeostasis and lipid metabolism, and an important target for the development of modern anti-diabetic drugs. However, current PPARγ-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 PPARγ modulator (SPPARγM), 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 PPARγ 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 SPPARγMs as safe and highly efficacious anti-diabetic drugs.

Graphical abstract: Identification and structural insight of an effective PPARγ modulator with improved therapeutic index for anti-diabetic drug discovery

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Article information


Submitted
31 Oct 2019
Accepted
20 Jan 2020
First published
21 Jan 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020, Advance Article
Article type
Edge Article

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

H. Jiang, X. E. Zhou, J. Shi, Z. Zhou, G. Zhao, X. Zhang, Y. Sun, K. Suino-Powell, L. Ma, H. Gao, X. Yu, J. Li, J. Li, K. Melcher, H. E. Xu and W. Yi, Chem. Sci., 2020, Advance Article , DOI: 10.1039/C9SC05487A

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