Affinity selection of double-click triazole libraries for rapid discovery of allosteric modulators for GLP-1 receptor

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.

Automated summary

The recently developed double-click reaction sequence is promising in expanding the number and diversity of 1,2,3-triazole derivatives. This study focused on the design, synthesis, and screening of double-click triazole libraries for drug discovery, using the glucagon-like-peptide-1 receptor as a challenging drug target. The streamlined synthesis of customized triazole libraries on an unprecedented scale led to the identification of positive allosteric modulators with unreported scaffolds. The unexpected binding mode of these modulators could provide insights into their mechanism of action.