Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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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)
  • Received : 2021.04.22
  • Accepted : 2021.05.26
  • Published : 2022.01.01
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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

Acknowledgement

This work was supported by a grant (NRF-2019M3E5D4069882) from the National Research Foundation, Ministry of Science and ICT, and a grant from the KRIBB Initiative Program.

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