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Rational Design by Structural Biology of Industrializable, Long-Acting Antihyperglycemic GLP-1 Receptor Agonists.
- Source :
-
Pharmaceuticals (14248247) . Jun2022, Vol. 15 Issue 6, p740-N.PAG. 17p. - Publication Year :
- 2022
-
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 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 14248247
- Volume :
- 15
- Issue :
- 6
- Database :
- Academic Search Index
- Journal :
- Pharmaceuticals (14248247)
- Publication Type :
- Academic Journal
- Accession number :
- 157796747
- Full Text :
- https://doi.org/10.3390/ph15060740