Targeting PAR1: Now What?

Protease-activated receptors (PARs) are a ubiquitously expressed class of G-protein-coupled receptors (GPCRs) that enable cells to respond to proteases in the extracellular environment in a nuanced and dynamic manner. PAR1 is the archetypal family member and has been the object of large-scale drug development programs since the 1990s. Vorapaxar and drotrecogin-alfa are approved PAR1-targeted therapeutics, but safety concerns have limited the clinical use of vorapaxar and questions regarding the efficacy of drotrecogin-alfa led to its withdrawal from the market. New understanding of mechanisms of PAR1 function, discovery of improved strategies for modifying PAR1 function, and identification of novel indications for PAR1 modulators have provided new opportunities for therapies targeting PAR1. In this review, we critically evaluate prospects for the next generation of PAR1-targeted therapeutics.