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bioRxiv · 10.1101/2022.04.11.487850

Rational design by structural biology of industrializable, long-acting antihyperglycemic GLP-1 receptor agonists

Sun, L.·Zheng, Z.-M.·Shao, C.-S.·Li, M.-W.·Wang, L.·Wang, H.·Zhao, G.-H.·Wang, P.
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Abstract

Glucagon-like peptide-1 (GLP-1) is easily degraded by dipeptidyl peptidase-4 (DPP-4) in the human body, limiting its therapeutic effect on type II diabetes. Therefore, improving GLP-1 receptor agonist (GLP-1RA) stability is a major obstacle for drug development. We analyzed human GLP-1, DPP-4, and GLP-1 receptor structures and designed three GLP-1RAs, which were introduced into fusion protein fragments and changed in the overall conformation. This modification effectively prevented GLP-1RAs from entering DPP-4 active center without affecting GLP-1Ras ability to bind to GLP-1R, the new GLP-1RA hypoglycemic effect lasting for >24 h. Through molecular modeling, molecular dynamics calculation, and simulation, possible tertiary structure models of GLP-1RAs were obtained; molecular docking with DPP-4 and GLP-1R showed access to the fusion protein. The overall conformational change of GLP-1RAs prevented DPP-4 binding, without affecting GLP-1Ras affinity to GLP-1R. This study provides important drug design ideas for GLP-1RA development and a new example for application of structural biology-based protein design in drug development.

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Sun, L., Zheng, Z.-M., Shao, C.-S., Li, M.-W., Wang, L., Wang, H., Zhao, G.-H., Wang, P.. 2022-04-11. Rational design by structural biology of industrializable, long-acting antihyperglycemic GLP-1 receptor agonists. https://doi.org/10.1101/2022.04.11.487850

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