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Affinity selection of double-click triazole libraries for rapid discovery of allosteric modulators for GLP-1 receptor | |
2023 | |
发表期刊 | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (IF:9.4[JCR-2023],10.8[5-Year]) |
ISSN | 0027-8424 |
EISSN | 1091-6490 |
卷号 | 120期号:11页码:e2220767120 |
发表状态 | 已发表 |
DOI | doi: 10.1073/pnas.2220767120 |
摘要 | The recently developed double-click reaction sequence [G. Meng et al., Nature 574, 86-89 (2019)] is expected to vastly expand the number and diversity of syntheti-cally accessible 1,2,3-triazole derivatives. However, it remains elusive how to rapidly navigate the extensive chemical space created by double-click chemistry for bioactive compound discovery. In this study, we selected a particularly challenging drug target, the glucagon-like-peptide-1 receptor (GLP-1R), to benchmark our new platform for the design, synthesis, and screening of double-click triazole libraries. First, we achieved a streamlined synthesis of customized triazole libraries on an unprecedented scale (composed of 38,400 new compounds). By interfacing affinity-selection mass spectrometry and functional assays, we identified a series of positive allosteric modu-lators (PAMs) with unreported scaffolds that can selectively and robustly enhance the signaling activity of the endogenous GLP-1(9-36) peptide. Intriguingly, we further revealed an unexpected binding mode of new PAMs which likely act as a molecular glue between the receptor and the peptide agonist. We anticipate the merger of dou-ble-click library synthesis with the hybrid screening platform allows for efficient and economic discovery of drug candidates or chemical probes for various therapeutic targets. |
关键词 | click chemistry affinity selection mass spectrometry GLP-1 receptor allosteric modulators |
URL | 查看原文 |
收录类别 | SCOPUS ; SCI |
语种 | 英语 |
资助项目 | National Key R&D Program of China["2022YFA1302902","2018YFA0507004"] ; National Natural Science Foundation of China["31971362","32171439"] ; Ministry of Science and Technology of China, Major State Basic Research Development Program of China[2021YFF0701704] ; Science and Technology Commission of Shanghai Municipality[21ZR1442500] ; Shanghai Sailing Program[21YF1428900] |
WOS研究方向 | Science & Technology - Other Topics |
WOS类目 | Multidisciplinary Sciences |
WOS记录号 | WOS:000959384500005 |
出版者 | NATL ACAD SCIENCES |
引用统计 | 正在获取...
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文献类型 | 期刊论文 |
条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/284205 |
专题 | iHuman研究所 生命科学与技术学院 iHuman研究所_特聘教授组_Raymond Stevens组 iHuman研究所_PI研究组_水雯箐组 iHuman研究所_PI研究组_Garth John Thompson组 生命科学与技术学院_博士生 |
通讯作者 | Sharpless, K. Barry; Dong, Jiajia; Shui, Wenqing |
作者单位 | 1.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Shanghai Jiao Tong Univ, Sch Chem & Chem Engn, Shanghai 200240, Peoples R China 5.Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA 6.Shanghai Jiao Tong Univ, Natl Facil Translat Med Shanghai, Inst Translat Med, Zhangjiang Inst Adv Study, Shanghai 200240, Peoples R China 7.Shanghai Artificial Intelligence Lab, Shanghai 200232, Peoples R China |
第一作者单位 | iHuman研究所; 生命科学与技术学院 |
通讯作者单位 | iHuman研究所; 生命科学与技术学院 |
第一作者的第一单位 | iHuman研究所 |
推荐引用方式 GB/T 7714 | Xin, Ye,Liu, Shuo,Liu, Yan,et al. Affinity selection of double-click triazole libraries for rapid discovery of allosteric modulators for GLP-1 receptor[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2023,120(11):e2220767120. |
APA | Xin, Ye.,Liu, Shuo.,Liu, Yan.,Qian, Zhen.,Liu, Hongyue.,...&Shui, Wenqing.(2023).Affinity selection of double-click triazole libraries for rapid discovery of allosteric modulators for GLP-1 receptor.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,120(11),e2220767120. |
MLA | Xin, Ye,et al."Affinity selection of double-click triazole libraries for rapid discovery of allosteric modulators for GLP-1 receptor".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 120.11(2023):e2220767120. |
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