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http://dx.doi.org/10.4062/biomolther.2021.078

Novel GPR43 Agonists Exert an Anti-Inflammatory Effect in a Colitis Model  

Park, Bi-Oh (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology)
Kang, Jong Soon (Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology)
Paudel, Suresh (College of Pharmacy, Korea University)
Park, Sung Goo (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology)
Park, Byoung Chul (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology)
Han, Sang-Bae (College of Pharmacy, Chungbuk National University)
Kwak, Young-Shin (College of Pharmacy, Korea University)
Kim, Jeong-Hoon (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology)
Kim, Sunhong (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology)
Publication Information
Biomolecules & Therapeutics / v.30, no.1, 2022 , pp. 48-54 More about this Journal
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 Gαi/o and Gαq/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 pre-existing 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.
Keywords
GPR43; Allosteric agonists; Anti-inflammation; NF-${\kappa}B$;
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