Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.
J Cardiovasc Pharmacol. 2022 Sep 1;80(3):378-385. doi: 10.1097/FJC.0000000000001236.
Pepducins are small-lipidated peptides designed from the intracellular loops of G protein-coupled receptors (GPCRs) that act in an allosteric manner to modulate the activity of GPCRs. Over the past 2 decades, pepducins have progressed initially from pharmacologic tools used to manipulate GPCR activity in an orthosteric site-independent manner to compounds with therapeutic potential that have even been used safely in phase 1 and 2 clinical trials in human subjects. The effect of pepducins at their cognate receptors has been shown to vary between antagonist, partial agonist, and biased agonist outcomes in various primary and clonal cell systems, with even small changes in amino acid sequence altering these properties and their receptor selectivity. To date, pepducins designed from numerous GPCRs have been studied for their impact on pathologic conditions, including cardiovascular diseases such as thrombosis, myocardial infarction, and atherosclerosis. This review will focus in particular on pepducins designed from protease-activated receptors, C-X-C motif chemokine receptors, formyl peptide receptors, and the β2-adrenergic receptor. We will discuss the historic context of pepducin development for each receptor, as well as the structural, signaling, pathophysiologic consequences, and therapeutic potential for each pepducin class.
肽聚糖是从小型脂肽设计的细胞内环的 G 蛋白偶联受体 (GPCRs) 以变构方式发挥作用来调节 GPCRs 的活性。在过去的 20 年中，肽聚糖最初从药理学工具用于操纵 GPCR 活动的变构位点独立方式发展到具有治疗潜力的化合物，甚至在人体的 1 期和 2 期临床试验中安全使用。肽聚糖在其同源受体的作用已被证明在各种原代和克隆细胞系统中存在拮抗剂、部分激动剂和偏向激动剂的结果，甚至氨基酸序列的微小变化也会改变这些特性及其受体选择性。迄今为止，已经研究了来自众多 GPCR 的肽聚糖对病理状况的影响，包括心血管疾病如血栓形成、心肌梗死和动脉粥样硬化。这篇综述将特别关注从蛋白酶激活受体、C-X-C 基序趋化因子受体、甲酰肽受体和β2-肾上腺素能受体设计的肽聚糖。我们将讨论每个受体的肽聚糖发展的历史背景，以及每个肽聚糖类的结构、信号转导、病理生理后果和治疗潜力。
