Critical aspects of maintaining glucose homeostasis in the face of chronic insulin resistance and type 2 diabetes (T2D) are increased insulin secretion and adaptive expansion of beta cell mass. Nutrient and hormone sensing G protein-coupled receptors are important mediators of these properties. A growing body of evidence now suggests that the G protein-coupled receptor, free fatty acid receptor 2 (FFA2), is capable of contributing to the maintenance of glucose homeostasis by acting at the pancreatic beta cell as well as at other metabolically active tissues. We have previously demonstrated that Gαq/11-biased agonism of FFA2 can potentiate glucose stimulated insulin secretion (GSIS) as well as promote beta cell proliferation. However, the currently available Gαq/11-biased agonists for FFA2 exhibit low potency, making them difficult to examine in vivo. This study sought to identify Gαq/11-biased FFA2-selective agonists with potent GSIS-stimulating effects. To do this, we generated an FFA2 homology model that was used to screen a library of 10 million drug-like compounds. Although FFA2 and the related short chain fatty acid receptor FFA3 share 52% sequence similarity, our virtual screen identified over 50 compounds with predicted selectivity and increased potency for FFA2 over FFA3. Subsequent in vitro calcium mobilization assays and GSIS assays resulted in the identification of a compound that can potentiate GSIS via activation of Gαq/11 with 100-fold increased potency compared with previously described Gαq/11-biased FFA2 agonists. These methods and findings provide a foundation for future discovery efforts to identify biased FFA2 agonists as potential T2D therapeutics.
- Islets Of Langerhans
- Receptors, G-protein-coupled
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SRV and RKM contributed equally.
Contributors Each author contributed to this article.
Funding BTL is supported by the National Institutes of Health under award number, R01DK104927-01A1, The University of Chicago DR&TC (P30DK020595) and Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Career Development (grant no. 1IK2BX001587-01). SRV is supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (F31DK102371), and the Northwestern University Program in Endocrinology, Diabetes and Hormone Action (NIH T32 DK007169). A part of this work was supported by the Northwestern University Medicinal and Synthetic Chemistry Cgpcsore (ChemCgpcsore the Center for Molecular Innovation and Drug Discovery (CMIDD), which is funded by the Chicago Biomedical Consortium with support from The Searle Funds aSearleChicago Community Trust and Cancer Center Support Grant P30 CA060553 from the National Cancer Institute awarded to the Robert H. Lurie Comprehe Lurie Cancer Center.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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