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- Title
Molecular dynamics-guided optimization of BGM0504 enhances dual-target agonism for combating diabetes and obesity.
- Authors
Yuan, Jiandong; Liu, Wenlang; Jiang, Xiaohui; Huang, Yangqing; Zong, Leilei; Ding, Haifeng; Shen, Xinyi; Sun, Yujia; Feng, Xiangyang; Li, Xionghao; Song, Yunsong; Gu, Jianing; Wang, Yuhuai; Liu, Hao; Zheng, Zheng
- Abstract
The dual activation of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) has emerged as a promising therapeutic strategy for managing type 2 diabetes and obesity. Tirzepatide, a dual agonist peptide, has exhibited superior clinical efficacy in glycemic and weight control compared to selective GLP-1R agonists. Nevertheless, the structural basis of Tirzepatide's extended half-life, attributed to an acylation side chain on the parent peptide, raises questions regarding its partial agonistic activity. Employing molecular dynamics simulations, we explored the dynamic processes of peptide-receptor interactions. We uncovered a crucial salt bridge between parent peptide and GLP-1R/GIPR at K20, a feature not discernible in cryo-electron microscopy structures. Building upon these insights, we developed an optimization strategy based on the parent peptide which involved repositioning the acylation side chain. The results of both in vitro and in vivo experiments demonstrated that the optimized peptide has twofold to threefold increase in agonistic activity compared to Tirzepatide while maintaining its extended half-life in plasma. This led to the design of BGM0504, which proved to be more effective than its predecessor, Tirzepatide, in both laboratory and animal studies.
- Subjects
MOLECULAR dynamics; TYPE 2 diabetes; PEPTIDES; GLYCEMIC control; OBESITY; DIABETES
- Publication
Scientific Reports, 2024, Vol 14, Issue 1, p1
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/s41598-024-66998-8