(Image from Juan Gaertner / Science Source)
Sepsis and COVID-19
Safer and more selective anti-inflammatory agents are urgently needed, in particular to prevent the dangerous thromboses, vascular damage, and strokes observed in victims of severe sepsis and COVID-19. Protease-activated receptors (PARs) are G-protein coupled receptors (GPCRs) with a unique mode of activation involving the cleavage of the N-terminus of the receptor by various proteases. Among other activities, these receptors play vital roles in the activation of platelet cells and the regulation of immune responses, and they also regulate the inflammatory responses of endothelial cells. We have identified and developed a class of small molecules called parmodulins that are allosteric modulators of PAR1, and have useful antithrombotic effects (in part via inhibition of PAR1 on platelets) and anti-inflammatory/barrier-protective effects (via endothelial PAR1). We are developing parmodulins with improved properties to investigate their potential for mitigating dangerous inflammatory conditions that can occur during serious infection, without adversely impacting normal immune function, which is a major liability of present drugs such as dexamethasone.