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

文献类型：期刊论文

作者Sun, Lei1,2; Zheng, Zhi-Ming2; Shao, Chang-Sheng2; Zhang, Zhi-Yong3; Li, Ming-Wei3; Wang, Li2; Wang, Han2; Zhao, Gen-Hai2; Wang, Peng1,2
刊名PHARMACEUTICALS
出版日期2022-06-01
卷号15
关键词glucagon-like peptide-1 GLP-1 receptor agonist functional protein design molecular dynamics simulation long-acting antihyperglycemic
DOI10.3390/ph15060740
通讯作者Zheng, Zhi-Ming(zmzheng@ipp.ac.cn) ; Wang, Peng(pengwang@ipp.ac.cn)
英文摘要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.
WOS关键词PEPTIDE-1 GLP-1 ; PROTEIN ; ANALOG ; PHARMACOKINETICS ; DEGRADATION ; MECHANISMS ; COMPLEXES ; EXENDIN-4 ; RESISTANT ; AFFINITY
资助项目Major Projects of Science and Technology of Anhui Province[202103a06020003] ; Key Research, China National Key Research and Development Program[2019YFA0904300] ; Key Research, China National Key Research and Development Program[2019YFA0904304] ; Development Plan of Anhui Province[1804b06020342] ; National Natural Science Foundation of China[91953101]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者MDPI
WOS记录号WOS:000816456000001
资助机构Major Projects of Science and Technology of Anhui Province ; Key Research, China National Key Research and Development Program ; Development Plan of Anhui Province ; National Natural Science Foundation of China
源URL[http://ir.hfcas.ac.cn:8080/handle/334002/129554]  
专题中国科学院合肥物质科学研究院
通讯作者Zheng, Zhi-Ming; Wang, Peng
作者单位1.Univ Sci & Technol China, Sci Isl Branch Grad Sch, Hefei 230026, Peoples R China
2.Chinese Acad Sci, Hefei Inst Phys Sci, Key Lab High Magnet Field & Ion Beam Phys Biol, Hefei 230031, Peoples R China
3.Univ Sci & Technol China, Natl Sci Ctr Phys Sci Microscale, Div Life Sci & Med, MOE Key Lab Membraneless Organelles & Cellular Dy, Hefei 230022, Peoples R China
推荐引用方式
GB/T 7714		 Sun, Lei,Zheng, Zhi-Ming,Shao, Chang-Sheng,et al. Rational Design by Structural Biology of Industrializable, Long-Acting Antihyperglycemic GLP-1 Receptor Agonists[J]. PHARMACEUTICALS,2022,15.
APA Sun, Lei.,Zheng, Zhi-Ming.,Shao, Chang-Sheng.,Zhang, Zhi-Yong.,Li, Ming-Wei.,...&Wang, Peng.(2022).Rational Design by Structural Biology of Industrializable, Long-Acting Antihyperglycemic GLP-1 Receptor Agonists.PHARMACEUTICALS,15.
MLA Sun, Lei,et al."Rational Design by Structural Biology of Industrializable, Long-Acting Antihyperglycemic GLP-1 Receptor Agonists".PHARMACEUTICALS 15(2022).

入库方式： OAI收割

来源：合肥物质科学研究院

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