Back to Search
Start Over
Affinity selection of double-click triazole libraries for rapid discovery of allosteric modulators for GLP-1 receptor.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 Mar 14; Vol. 120 (11), pp. e2220767120. Date of Electronic Publication: 2023 Mar 09. - Publication Year :
- 2023
-
Abstract
- 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 synthetically 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 modulators (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 double-click library synthesis with the hybrid screening platform allows for efficient and economic discovery of drug candidates or chemical probes for various therapeutic targets.
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 120
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 36893261
- Full Text :
- https://doi.org/10.1073/pnas.2220767120