G蛋白偶联受体
肽
受体
生物化学
化学
细胞生物学
生物
作者
Sam Lear,Zaid Amso,Weijun Shen
出处
期刊:Methods in Enzymology
日期:2019-01-01
卷期号:: 183-200
被引量:10
标识
DOI:10.1016/bs.mie.2019.02.008
摘要
G protein-coupled receptors (GPCRs) play a key role in signal transduction and human pathophysiological processes. Family B GPCRs are activated by a number of secreted peptide hormones, and engineering of these peptide ligands in order to improve stability and half-life, and therefore clinical efficacy has proven successful for drug discovery. In this chapter we discuss a novel peptide engineering strategy that combines peptide side chain stapling with covalent incorporation of a serum protein binding motif in a single step. The application of this approach to the enhancement of the helicity and stability of GLP-1R peptide agonists, resulting in their improved in vitro potencies, in vivo half-lives and ultimately efficacies, will be described. Discussion of the stapling technology and target selection rationale, peptide engineering and final biological characterization of the long-acting agonists will also be provided.
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