Effects of site-directed mutagenesis of GLP-1 and glucagon receptors on signal transduction activated by dual and triple agonists  

作　　者：Sanaz Darbalaei Ru-lue Chang Qing-tong Zhou Yan Chen An-tao Dai Ming-wei Wang De-hua Yang 

机构地区：[1]The National Center for Drug Screening and CAS Key Laboratory of Receptor Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences(CAS),Shanghai 201203,China [2]University of Chinese Academy of Sciences,Beijing 100049,China [3]School of Pharmacy,Fudan University,Shanghai 201203,China [4]Department of Pharmacology,School of Basic Medical Sciences,Fudan University,Shanghai 200032,China [5]Research Center for Deepsea Bioresources,Sanya 572025,China [6]Department of Chemistry,School of Science,The University of Tokyo,Tokyo 113-0033,Japan

出　　处：《Acta Pharmacologica Sinica》2023年第2期421-433,共13页中国药理学报（英文版）

基　　金：supported by National Natural Science Foundation of China 81872915(MWI),82073904(MW),82121005(DY),81973373(DY),21704064(QZ);National Science&Technology Major Project of China-Key New Drug Creation and Manufacturing Program 2018ZX09735-001(MW),2018ZX09711002-002-005(DY);National Science&Technology Major Project of China-Innovation 2030 for Brain Science and Brain-Inspired Technology 2021ZD0203400(QZ);the National Key Basic Research Program of China 2018YFA0507000(MW);Novo Nordisk-CAS Research Fund grant NNCAS-2017-1-CC(DY)and SA-SIBS Scholarship Program(IDY).

摘　　要：The paradigm of one drug against multiple targets,known as unimolecular polypharmacology,offers the potential to improve efficacy while overcoming some adverse events associated with the treatment.This approach is best exemplified by targeting two or three class B1 G protein-coupled receptors,namely,glucagon-like peptide-1 receptor(GLP-1R),glucagon receptor(GCGR)and glucose-dependent insulinotropic polypeptide receptor for treatment of type 2 diabetes and obesity.Some of the dual and triple agonists have already shown initial successes in clinical trials,although the molecular mechanisms underlying their multiplexed pharmacology remain elusive.In this study we employed structure-based site-directed mutagenesis together with pharmacological assays to compare agonist efficacy across two key signaling pathways,cAMP accumulation and ERK1/2 phosphorylation(pERK1/2).Three dual agonists(peptide 15,MEDI0382 and SAR425899)and one triple agonist(peptide 20)were evaluated at GLP-1R and GCGR,relative to the native peptidic ligands(GLP-1 and glucagon).Our results reveal the existence of residue networks crucial for unimolecular agonist-mediated receptor activation and their distinct signaling patterns,which might be useful to the rational design of biased drug leads.

关 键 词：glucagon-like peptide-1 receptor glucagon receptor dual and triple agonist cAMP PERK1/2 unimolecular polypharmacology 

分 类 号：R58[医药卫生—内分泌]