Rational Design by Structural Biology of Industrializable, Long-Acting Antihyperglycemic GLP-1 Receptor Agonists

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 15; no. 6; p. 740
• Main Authors: Sun, Lei, Zheng, Zhi-Ming, Shao, Chang-Sheng, Zhang, Zhi-Yong, Li, Ming-Wei, Wang, Li, Wang, Han, Zhao, Gen-Hai, Wang, Peng
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 13.06.2022; MDPI
• Subjects: Amino acids; Binding sites; Chemical bonds; Design; Diabetes; E coli; Enzymes; Fermentation; functional protein design; GLP-1 receptor agonist; glucagon-like peptide-1; Glucose; Insulin resistance; Kinases; long-acting antihyperglycemic; molecular dynamics simulation; Mutation; Peptides; Plasmids; Proteins; GLP-1 receptor agonist; long-acting antihyperglycemic; functional protein design; glucagon-like peptide-1; molecular dynamics simulation
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph15060740

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 the 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.