Effects of site-directed mutagenesis of GLP-1 and glucagon receptors on signal transduction activated by dual and triple agonists
文献类型：期刊论文
| 作者 | Darbalaei, Sanaz5,6,7; Chang, Ru-lue4; Zhou, Qing-tong3; Chen, Yan3; Dai, An-tao6,7; Wang, Ming-wei1,2,3,4 ; Yang, De-hua2,5,6,7
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2022-08-11 |
| 页码 | 13 |
| 关键词 | glucagon-like peptide-1 receptor glucagon receptor dual and triple agonist cAMP pERK1/2 unimolecular polypharmacology |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/s41401-022-00962-y |
| 通讯作者 | Wang, Ming-wei(mwwang@simm.ac.cn) ; Yang, De-hua(dhyang@simm.ac.cn) |
| 英文摘要 | 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. |
| WOS关键词 | PROTEIN-COUPLED RECEPTORS ; PEPTIDE-1 RECEPTOR ; LIGAND-BINDING ; CORRECTS OBESITY ; BIASED AGONISM ; DOMAIN ; RECOGNITION ; POLYPEPTIDE ; MECHANISMS ; RESIDUES |
| 资助项目 | National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[82073904] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[81973373] ; National Natural Science Foundation of China[21704064] ; National Science & Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09735-001] ; National Science & Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-005] ; National Science & Technology Major Project of China-Innovation 2030 for Brain Science and Brain-Inspired Technology[2021ZD0203400] ; National Key Basic Research Program of China[2018YFA0507000] ; Novo Nordisk-CAS Research Fund[NNCAS-2017-1-CC] ; SA-SIBS Scholarship Program |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000839515900001 |
| 出版者 | NATURE PUBL GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/302272]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Wang, Ming-wei; Yang, De-hua |
| 作者单位 | 1.Univ Tokyo, Sch Sci, Dept Chem, Tokyo 1130033, Japan 2.Res Ctr Deepsea Bioresources, Sanya 572025, Peoples R China 3.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 200032, Peoples R China 4.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 7.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Darbalaei, Sanaz,Chang, Ru-lue,Zhou, Qing-tong,et al. Effects of site-directed mutagenesis of GLP-1 and glucagon receptors on signal transduction activated by dual and triple agonists[J]. ACTA PHARMACOLOGICA SINICA,2022:13. |
| APA | Darbalaei, Sanaz.,Chang, Ru-lue.,Zhou, Qing-tong.,Chen, Yan.,Dai, An-tao.,...&Yang, De-hua.(2022).Effects of site-directed mutagenesis of GLP-1 and glucagon receptors on signal transduction activated by dual and triple agonists.ACTA PHARMACOLOGICA SINICA,13. |
| MLA | Darbalaei, Sanaz,et al."Effects of site-directed mutagenesis of GLP-1 and glucagon receptors on signal transduction activated by dual and triple agonists".ACTA PHARMACOLOGICA SINICA (2022):13. |
入库方式： OAI收割
来源：上海药物研究所
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