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])
ISSN0027-8424
EISSN1091-6490
卷号120期号:11页码:e2220767120
发表状态已发表
DOIdoi: 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
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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
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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
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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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