Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2021.078
Novel GPR43 Agonists Exert an Anti-Inflammatory Effect in a Colitis Model
Bi-Oh Park1,2, Jong Soon Kang3, Suresh Paudel4, Sung Goo Park1,5, Byoung Chul Park1,6, Sang-Bae Han2, Young-Shin Kwak4,*,ψ, Jeong-Hoon Kim1,5,* and Sunhong Kim1,7,*,ψ
1Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141,
2College of Pharmacy, Chungbuk National University, Cheongju 28160,
3Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116,
4College of Pharmacy, Korea University, Sejong 30019,
5Department of Functional Genomics, KRIBB School of Biological Science, Korea University of Science and Technology, Daejeon 34113,
6Department of Proteome Structural Biology, KRIBB School of Biological Science, Korea University of Science and Technology, Daejeon 34113,
7Department of Biomolecular Science, KRIBB School of Biological Science, Korea University of Science and Technology, Daejeon 34113, Republic of Korea
*E-mail: youngshin@lgchem.com (Kwak YS),
jhoonkim@kribb.re.kr (Kim JH), skimbio@lgchem.com (Kim S)
Tel: +82-2-6987-4700 (Kwak YS), +82-42-860-4264 (Kim JH),
+82-2-6987-5505 (Kim S)
Fax: +82-2-6987-4811 (Kwak YS), +82-42-860-4598 (Kim JH),
+82-2-6987-4811 (Kim S)
ψPresent Address
Drug Discovery Center, Life Sciences, LG Chem, Seoul 07796, Republic of Korea
Received: April 22, 2021; Revised: May 20, 2021; Accepted: May 26, 2021; Published online: June 25, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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 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.
Keywords: GPR43, Allosteric agonists, Anti-inflammation, NF-κB


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