Novel GPR43 Agonists Exert an Anti-Inflammatory Effect in a Colitis Model
10.4062/biomolther.2021.078
- Author:
Bi-Oh PARK
1
;
Jong Soon KANG
;
Suresh PAUDEL
;
Sung Goo PARK
;
Byoung Chul PARK
;
Sang-Bae HAN
;
Young-Shin KWAK
;
Jeong-Hoon KIM
;
Sunhong KIM
Author Information
1. Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
- Publication Type:Original Article
- From:Biomolecules & Therapeutics
2022;30(1):48-54
- CountryRepublic of Korea
- Language:English
-
Abstract:
GPR43 (also known as FFAR2), a metabolite-sensing G-protein-coupled receptor stimulated by short-chain fatty acid (SCFA) ligands is involved in innate immunity and metabolism. GPR43 couples with Gα i/o and Gα q/11 heterotrimeric proteins and is capable of decreasing cyclic AMP and inducing Ca2+ flux. The GPR43 receptor has additionally been shown to bind β-arrestin 2 and inhibit inflammatory pathways, such as NF-κB. However, GPR43 shares the same ligands as GPR41, including acetate, propionate, and butyrate, and determination of its precise functions in association with endogenous ligands, such as SCFAs alone, therefore remains a considerable challenge. In this study, we generated novel synthetic agonists that display allosteric modulatory effects on GPR43 and downregulate NF-κB activity. In particular, the potency of compound 187 was significantly superior to that of preexisting compounds in vitro. However, in the colitis model in vivo, compound 110 induced more potent attenuation of inflammation. These novel allosteric agonists of GPR43 clearly display anti-inflammatory potential, supporting their clinical utility as therapeutic drugs.
