Targeting biased signaling by PAR1: function and molecular mechanism of parmodulins

• Published in: Blood Vol. 141; no. 22; pp. 2675 - 2684
• Main Authors: Künze, Georg, Isermann, Berend
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2023
• Subjects: Animals; Anti-Inflammatory Agents; Blood Coagulation; Endothelial Cells - metabolism; Mice; Peptide Hydrolases - metabolism; Receptor, PAR-1 - metabolism; Signal Transduction
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2023019775

[Display omitted] 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. Protease-activated receptor-1 (PAR1) is a 7 transmembrane, G protein–coupled receptor expressed by endothelial cells that is a therapeutic target for cardiovascular disease, as it mediates thrombin-dependent platelet activation. PAR1 activation depends on proteolytic cleavage, and PAR-1 signaling can be biased, depending on how it is cleaved. New agents targeting PAR1, parmodulins, exploit this to selectively affect PAR1 signaling for therapeutic benefit. Künze and Isermann review the discovery, structure, mechanism of activity, and potential clinical use of parmodulins.