Evaluation of biased agonism mediated by dual agonists of the GLP-1 and glucagon receptors
文献类型：期刊论文
| 作者 | Darbalaei, Sanaz1,2; Yuliantie, Elita1,2; Dai, Antao1; Chang, Rulue3; Zhao, Peishen4; Yang, Dehua1,2 ; Wang, Ming-Wei1,2,3,5; Sexton, Patrick M.4; Wootten, Denise4
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| 刊名 | BIOCHEMICAL PHARMACOLOGY
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| 出版日期 | 2020-10-01 |
| 卷号 | 180页码:16 |
| 关键词 | G protein-coupled receptor Glucagon-like peptide-1 receptor Glucagon receptor Biased agonism Unimolecular dual agonist |
| ISSN号 | 0006-2952 |
| DOI | 10.1016/j.bcp.2020.114150 |
| 通讯作者 | Wang, Ming-Wei(mwwang@simm.ac.cn) ; Sexton, Patrick M.(Patrick.sexton@monash.edu) ; Wootten, Denise(denise.wootten@monash.edu) |
| 英文摘要 | Metabolic diseases such as obesity, diabetes, and their comorbidities have converged as one of the most serious health concerns on a global scale. Selective glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists are one of the major therapeutics for type 2 diabetes and obesity. Polypharmacological approaches that enable modulation of multiple metabolic targets in a single drug have emerged as a potential avenue to improve therapeutic outcomes. Among numerous peptides under development are those targeting the GLP-1R and either the glucagon receptor (GCGR), glucose-dependent insulinotropic peptide receptor (GIPR) or all 3 receptors, as dual- or tri- peptide agonists. Despite many of them entering into clinical trials, current development has been based on only a limited understanding of the spectrum of potential pharmacological properties of these ligands beyond binding selectivity. In the present study, we examined the potential for agonists that target both GLP-1R and GCGR to exhibit biased agonism, comparing activity across proximal activation of Gs protein, cAMP accumulation, pERK1/2 and beta-arrestin recruitment. Three distinct dual agonists that have different relative cAMP production potency for GLP-1R versus GCGR, "peptide 15", MEDI0382 and SAR425899, and one triagonist of the GLP-1R, GCGR and GIPR were examined. We demonstrated that all novel peptides have distinct biased agonism profiles relative to either of the cognate agonists of the receptors, and to each other. This is an important feature of the pharmacology of this drug class that needs to be considered alongside selectivity, bioavailability and pharmacokinetics for rational optimization of new therapeutics. |
| WOS关键词 | PEPTIDE-1 ; PHARMACOLOGY ; OXYNTOMODULIN ; MECHANISMS ; PHYSIOLOGY ; OBESITY ; HEALTH |
| 资助项目 | National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[81973373] ; National Natural Science Foundation of China[81773792] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09735-001] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002-002-005] ; National Key R&D Program of China[2018YFA0507000] ; Novo Nordisk-CAS Research Fund[NNCAS-2017-1-CC] ; National Medical Research Council of Australia (NHMRC)[1184726] ; National Medical Research Council of Australia (NHMRC)[1126857] ; National Medical Research Council of Australia (NHMRC)[1150083] ; NHMRC[1154434] ; NHMRC[1160076] ; UCAS Scholarship for International Students ; CAS-TWAS President's Fellowship for International Doctoral Students |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000579310000019 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/291356]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Wang, Ming-Wei; Sexton, Patrick M.; Wootten, Denise |
| 作者单位 | 1.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China 4.Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol Theme, Parkville, Vic 3052, Australia 5.Fudan Univ, Sch Basic Med Sci, Shanghai 200032, Peoples R China |
| 推荐引用方式 GB/T 7714 | Darbalaei, Sanaz,Yuliantie, Elita,Dai, Antao,et al. Evaluation of biased agonism mediated by dual agonists of the GLP-1 and glucagon receptors[J]. BIOCHEMICAL PHARMACOLOGY,2020,180:16. |
| APA | Darbalaei, Sanaz.,Yuliantie, Elita.,Dai, Antao.,Chang, Rulue.,Zhao, Peishen.,...&Wootten, Denise.(2020).Evaluation of biased agonism mediated by dual agonists of the GLP-1 and glucagon receptors.BIOCHEMICAL PHARMACOLOGY,180,16. |
| MLA | Darbalaei, Sanaz,et al."Evaluation of biased agonism mediated by dual agonists of the GLP-1 and glucagon receptors".BIOCHEMICAL PHARMACOLOGY 180(2020):16. |
入库方式： OAI收割
来源：上海药物研究所
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