Stereoselective synthesis, biological evaluation, and modeling of novel bile acid-derived G-protein coupled bile acid receptor 1 (GP-BAR1, TGR5) agonists.
GP-BAR1 (also known as TGR5), a novel G-protein coupled receptor regulating various non-genomic functions via bile acid signaling, has emerged as a promising target for metabolic disorders, including obesity and type II diabetes. However, given that many bile acids (BAs) are poorly tolerated for systemic therapeutic use, there is significant need to develop GP-BAR1 agonists with improved potency and specificity and there also is significant impetus to develop a stereoselective synthetic methodology for GP-BAR1 agonists. Here, we report the development of highly stereo-controlled strategies to investigate a series of naturally occurring bile acid derivatives with markedly enhanced GP-BAR1 activity. These novel GP-BAR1 agonists are evaluated in vitro using luciferase-based reporter and cAMP assays to elucidate their biological properties. In vivo studies revealed that the GP-BAR1 agonist 23(S)-m-LCA increased intestinal GLP-1 transcripts by 26-fold. Additionally, computational modeling studies of selected ligands that exhibit enhanced potency and specificity for GP-BAR1 provide information on potential binding sites for these ligands in GP-BAR1.
Department of Diabetes and Metabolic Diseases Research, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA. Electronic address: dyu@coh.org.
Donna D
DD
Yu
Department of Diabetes and Metabolic Diseases Research, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA; Department of Pharmaceutical Sciences, West Coast University School of Pharmacy, Los Angeles, CA 90004, USA. Electronic address: ksousa@westcoastuniversity.edu.
Kyle M
KM
Sousa
Department of Chemistry and Biochemistry, The University of Mississippi, University, MS 38677, USA.
Daniell L
DL
Mattern
Department of Immunology, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
Jeffrey
J
Wagner
Department of Diabetes and Metabolic Diseases Research, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
Xianghui
X
Fu
Department of Immunology, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
Nagarajan
N
Vaidehi
Department of Diabetes and Metabolic Diseases Research, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
Barry M
BM
Forman
Department of Diabetes and Metabolic Diseases Research, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA. Electronic address: whuang@coh.org.
Wendong
W
Huang
D000595:Amino Acid Sequence; D000818:Animals; D001647:Bile Acids and Salts / Q000138:chemical synthesis* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics; D013237:Stereoisomerism
D001647:Bile Acids and Salts; C473772:GPBAR1 protein, human; D043562:Receptors, G-Protein-Coupled