Annual Review of Pharmacology and Toxicology ( IF 11.2 ) Pub Date : 2017-01-06 00:00:00 , DOI: 10.1146/annurev-pharmtox-011613-140016 Justin R. Hamilton 1 , JoAnn Trejo 2
Protease-activated receptors (PARs) are a unique class of G protein–coupled receptors (GPCRs) that transduce cellular responses to extracellular proteases. PARs have important functions in the vasculature, inflammation, and cancer and are important drug targets. A unique feature of PARs is their irreversible proteolytic mechanism of activation that results in the generation of a tethered ligand that cannot diffuse away. Despite the fact that GPCRs have proved to be the most successful class of druggable targets, the development of agents that target PARs specifically has been challenging. As a consequence, researchers have taken a remarkable diversity of approaches to develop pharmacological entities that modulate PAR function. Here, we present an overview of the diversity of therapeutic agents that have been developed against PARs. We further discuss PAR biased signaling and the influence of receptor compartmentalization, posttranslational modifications, and dimerization, which are important considerations for drug development.
中文翻译:
蛋白酶激活受体药物开发的挑战与机遇
蛋白酶激活受体(PARs)是一类独特的G蛋白偶联受体(GPCR),可将细胞对胞外蛋白酶的反应转导。PAR在脉管系统,炎症和癌症中具有重要功能,并且是重要的药物靶标。PAR的独特特征是其不可逆的蛋白水解激活机制,导致无法扩散的束缚配体的产生。尽管事实证明GPCR是最成功的可药物靶向类型,但开发专门针对PAR的药物仍具有挑战性。结果,研究人员采取了多种方法来开发可调节PAR功能的药理实体。在这里,我们概述了针对PARs开发的多种治疗药物。