Abstract

Preclinical Optimization Of Type 2 Serine Protease Inhibitors For The Treatment Of Influenza - An Academic Drug Discovery Example

Eric Marsault, Professor, University of Sherbrook

Influenza is a leading cause of hospitalization and death, and occasionally the source of pandemics. Besides vaccination, current treatments target viral proteins and are associated with increasing resistance. Proteolytic cleavage of the virus hemagglutinin by host cell proteases is a pivotal early step of infectivity. Type II transmembrane serine proteases (TTSP) expressed in the lung can mediate the maturation of the influenza virus, triggering an obligatory step in airway cell invasion. We present herein potent and selective inhibitors of TTSP, with a particular emphasis on matriptase. These inhibitors mimic the cleavage sequence of matriptase and were equipped with a serine trap to provide a slow, tight binding mechanism of action. Their efficacy and selectivity in vitro their ability to reduce virus replication of H1 and H3 subtypes in human epithelial respiratory cells (Calu-3) as well as their efficacy in vivo will be presented. This project is a collaboration between three complementary research groups from Université de Sherbrooke (Québec, Canada) and the drug discovery organization Neomed.