Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
Sosei Heptares, Granta Park, Cambridge, UK.
Nat Rev Drug Discov. 2020 Jun;19(6):389-413. doi: 10.1038/s41573-020-0062-z. Epub 2020 Mar 19.
Dysregulation of peptide-activated pathways causes a range of diseases, fostering the discovery and clinical development of peptide drugs. Many endogenous peptides activate G protein-coupled receptors (GPCRs) - nearly 50 GPCR peptide drugs have been approved to date, most of them for metabolic disease or oncology, and more than 10 potentially first-in-class peptide therapeutics are in the pipeline. The majority of existing peptide therapeutics are agonists, which reflects the currently dominant strategy of modifying the endogenous peptide sequence of ligands for peptide-binding GPCRs. Increasingly, novel strategies are being employed to develop both agonists and antagonists, to both introduce chemical novelty and improve drug-like properties. Pharmacodynamic improvements are evolving to allow biasing ligands to activate specific downstream signalling pathways, in order to optimize efficacy and reduce side effects. In pharmacokinetics, modifications that increase plasma half-life have been revolutionary. Here, we discuss the current status of the peptide drugs targeting GPCRs, with a focus on evolving strategies to improve pharmacokinetic and pharmacodynamic properties.
肽激活途径的失调会导致一系列疾病，这促进了肽类药物的发现和临床开发。许多内源性肽激活 G 蛋白偶联受体 (GPCR) - 迄今为止，已有近 50 种 GPCR 肽类药物获得批准，其中大多数用于代谢疾病或肿瘤学，超过 10 种潜在的首创肽类治疗药物正在研发中。大多数现有的肽类治疗药物都是激动剂，这反映了目前修饰配体与肽结合 GPCR 的内源性肽序列的主导策略。越来越多的新策略被用于开发激动剂和拮抗剂，以引入化学新颖性并改善药物样性质。药效学的改进正在发展，以允许偏向配体激活特定的下游信号通路，从而优化疗效并减少副作用。在药代动力学方面，增加血浆半衰期的修饰是革命性的。在这里，我们讨论了靶向 GPCR 的肽类药物的现状，重点讨论了改善药代动力学和药效学性质的不断发展的策略。
