Development of pan-coronavirus antivirals by targeting host kinases.

The emergence of three significant human coronaviruses (SARS-CoV, MERS-CoV, SARS-CoV-2) in recent years demonstrates the constant risk of zoonotic spillover events and emergence of human pathogens that can cause devastating outcomes.

Developing novel broad-spectrum antivirals that can be rapidly deployed to treat coronavirus infections is particularly critical given the absence of a pan-coronavirus vaccine or vaccines against (as yet unknown) novel human coronaviruses.

I propose to investigate the broad pan-coronavirus antiviral activity of molecules called proteolysis-targeting chimeras (PROTACs) that target and degrade key host kinase proteins required for coronavirus infections.

Coronaviruses elicit large-scale changes in host cell protein phosphorylation, and kinases that regulate these pathways are important antiviral drug targets. Host kinases play key roles in replication and entry across the coronavirus family.

As PROTACs degrade the target proteins, they are likely to be longer-acting and have higher antiviral efficacies than corresponding small-molecule kinase inhibitors.

I have previously identified PROTACs (targeting EGFR, Cdk4/6, and p38a) that efficiently inhibit seasonal human coronavirus OC43 and 229E infections.

The objectives of this project will be to 1) assess pan-coronavirus activity of kinase-targeting PROTACs against pandemic coronaviruses in a range of infection models; 2) investigate the mechanism of action by probing their role in the viral lifecycle, and evaluating the kinetics of their activity.

Determining the efficacy of kinase-targeting PROTACs to inhibit coronavirus infection will have important implications for the development of novel antivirals, while also providing a tool to discover exciting new biology about coronaviruses and virus-host interactions.