Challenges and Opportunities in Protease-Activated Receptor Drug Development.
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.
Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.
Justin R
JR
Hamilton
Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California 92093; email: joanntrejo@ucsd.edu.
JoAnn
J
Trejo
D000818:Animals; D055808:Drug Discovery / Q000379:methods* / Q000639:trends; D006801:Humans; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology; D044462:Receptors, Proteinase-Activated / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
C581100:GB88 compound; D009842:Oligopeptides; D044462:Receptors, Proteinase-Activated
biased signaling; dimerization; endothelial; platelet; thrombin