Institute for Drug Discovery, Medical Faculty, University of Leipzig, Leipzig, Germany.
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital, Leipzig, Germany.
Blood. 2023 Jun 1;141(22):2675-2684. doi: 10.1182/blood.2023019775.
The G protein-coupled receptor (GPCR) protease-activated receptor 1 (PAR1) is a therapeutic target that was originally pursued with the aim of restricting platelet activation and the burden of cardiovascular diseases. In clinical studies, the use of orthosteric PAR1 inhibitors was associated with an increased risk of hemorrhage, including intracranial hemorrhage. Because (1) PAR1 is expressed by various cell types, including endothelial cells, (2) conveys in mice a physiological indispensable function for vascular development during embryogenesis, and (3) is subject to biased signaling dependent on the activating proteases, orthosteric PAR1 inhibition may be associated with unwanted side effects. Alternatively, the protease-activated protein C (aPC) and its variants can promote valuable anti-inflammatory signaling via PAR1. Most recently, small molecule allosteric modulators of PAR1 signaling, called parmodulins, have been developed. Parmodulins inhibit coagulation and platelet activation yet maintain cytoprotective effects typically provoked by PAR1 signaling upon the activation by aPC. In this study, we review the discovery of parmodulins and their preclinical data, summarize the current knowledge about their mode of action, and compare the structural interaction of parmodulin and PAR1 with that of other intracellularly binding allosteric GPCR modulators. Thus, we highlight the pharmaceutical potential and challenges associated with the future development of parmodulins.
G 蛋白偶联受体（GPCR）蛋白酶激活受体 1（PAR1）是一个治疗靶点，最初的目标是限制血小板激活和心血管疾病的负担。在临床研究中，使用正位 PAR1 抑制剂与出血风险增加有关，包括颅内出血。由于（1）PAR1 表达于多种细胞类型，包括内皮细胞，（2）在小鼠中传递胚胎发生期间血管发育的生理必需功能，以及（3）受激活蛋白酶的偏倚信号传导的影响，正位 PAR1 抑制可能与不良副作用有关。相反，蛋白酶激活蛋白 C（aPC）及其变体可以通过 PAR1 促进有价值的抗炎信号传导。最近，已经开发出 PAR1 信号的小分子别构调节剂，称为 parmodulins。Parmodulins 抑制凝血和血小板激活，但在 aPC 激活时通过 PAR1 信号传导保持通常引发的细胞保护作用。在这项研究中，我们回顾了 parmodulins 的发现及其临床前数据，总结了它们作用模式的当前知识，并比较了 parmodulin 和 PAR1 的结构相互作用与其他细胞内结合的别构 GPCR 调节剂的结构相互作用。因此，我们强调了与 parmodulins 的未来开发相关的药物潜力和挑战。
