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Project

Host proteases at the interface between humans and SARS-CoV-2: Focus on TMPRSS2 as a therapeutic target.

The coronavirus SARS-CoV-2, causative of COVID-19, currently causes an unprecedented pandemic.Human SARS-CoV-2 infections are enabled by two events that occur at the host-virus interface. First,viral attachment to host cells is mediated by an interaction between the SARS-CoV-2 'spike' proteinand its host receptor angiotensin converting enzyme 2 (ACE2).Next, the virus is "primed" for host cellentry through proteolytic cleavage of SARS-CoV-2-spike protein by other surface-exposed hostproteases such as TMPRSS2. Inhibition of TMPRSS2-enabled "priming" negatively impacts SARS-CoV-2infectivity. Unfortunately, the currently available TMPRSS2 inhibitors (such as camostat) are nonspecific.For the development of inhibitors with an increased specificity and high potency, a betterknowledge of the characteristics of the protease are urgently needed.This project aims to lay the indispensable foundation for the rational design of specific TMPRSS2inhibitors in the battle against SARS-CoV-2 and COVID-19.This will be realized in two work packages (WPs) and 6 interrelated and measurable deliverables (D).The project will focus on following research questions: (1) What is the extended substrate specificityof TMPRSS2? and (2) What is the correlation between TMPRSS2 inhibition and neutralization of SARSCoV-2 infectivity in vitro? The deliverables of the project include the availability of active recombinanthuman TMPRSS2, methods to quantify its activity, data on the extended substrate specificity and onthe inhibitory potency of a set of 100 compounds from the library of protease inhibitors of theUAntwerp research group on Medicinal Chemistry (UAMC). The correlation of the inhibitory potencyof these compounds with their effect on in vitro infectivity of SARS-CoV-2, together with data onextended TMPRSS2 substrate specificity, are an indispensable prerequisite for optimal planning oflarger collaborative projects on host protease targeting as a therapeutic approach in the fight againstCOVID-19. Moreover, given the recently acquired expertise in structural biology in our lab, this projectwill lay a solid foundation for future structural studies of hit compounds in complex with TMPRSS2,which can in turn fuel rational drug design to generate more potent and specific compounds.
Date:1 Jun 2020 →  31 May 2021
Keywords:COVID-19, CORONA VIRUS, TMPRSS-2, PROTEASES
Disciplines:Proteins, Drug discovery and development not elsewhere classified