Jayakody Tharindunee, Budagoda Dinath Kavishka, Mendis Krishan, Dilshan Withanage Dhanuka, Bethmage Duvindu, Dissasekara Rashmi, Dawe Gavin Stewart
Department of Chemistry, University of Colombo, P.O. Box 1490, Colombo 00300, Sri Lanka.
Department of Chemistry, University of Colombo, P.O. Box 1490, Colombo 00300, Sri Lanka; The Graduate School, University of Connecticut Health Center, Farmington, CT 06030, USA.
Pharmacol Ther. 2025 May;269:108806. doi: 10.1016/j.pharmthera.2025.108806. Epub 2025 Jan 29.
G protein-coupled receptors (GPCRs) are dynamic membrane receptors that transduce extracellular signals to the cell interior by forming a ligand-receptor-effector (ternary) complex that functions via allosterism. Peptides constitute an important class of ligands that interact with their cognate GPCRs (peptide-GPCRs) to form the ternary complex. "Biased agonism", a therapeutically relevant phenomenon exhibited by GPCRs owing to their allosteric nature, has also been observed in peptide-GPCRs, leading to the development of selective therapeutics with fewer side effects. In this review, we have focused on the structural basis of signalling bias at peptide-GPCRs of classes A and B, and reviewed the therapeutic relevance of bias at peptide-GPCRs, with the hope of contributing to the discovery of novel biased peptide drugs.
G蛋白偶联受体（GPCRs）是动态膜受体，通过形成经由变构起作用的配体 - 受体 - 效应器（三元）复合物将细胞外信号转导至细胞内部。肽构成了一类重要的配体，它们与其同源GPCRs（肽 - GPCRs）相互作用以形成三元复合物。“偏向激动作用”是GPCRs因其变构性质而表现出的一种与治疗相关的现象，在肽 - GPCRs中也已观察到，这导致了副作用较少的选择性治疗药物的开发。在本综述中，我们重点关注了A类和B类肽 - GPCRs信号偏向的结构基础，并综述了肽 - GPCRs中偏向的治疗相关性，希望有助于发现新型偏向性肽药物。
