Uncovering cellular substrates of 3C-like proteases to identify conserved virus-host interactions as antiviral targets

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Many of the viruses disrupting society today are distantly related: these include SARS-CoV-2, the agent behind the COVID-19 pandemic, and norovirus which causes epidemics of gastroenteritis. These viruses are members of the coronavirus and calicivirus families, and along with the picornavirus family share common elements, including an enzyme: a 3C or 3C-like protease, which cleaves viral and cellular proteins.In the majority of cases, we do not know which human cell proteins are targeted by these 3C-like proteases during viral infection. For this proposal, I will identify all the cellular proteins cleaved by 3C-like proteases from a range of RNA viruses encompassing important human pathogens. I will test these proteins to see if they are essential for virus infection and then discover how cleavage by 3C-like proteases modulates the function of the target proteins in virus-infected cells. Most current antiviral strategies target viral proteins with an inhibitor (direct-acting antivirals). However, generating direct-acting antivirals against viral targets for a yet-unknown disease X that has yet to appear represents a formidable challenge, as it requires designing drugs against targets that may be similar, but by their very definition, are unknowable beforehand. An alternative approach would employ host-targeting antivirals, which seek to inhibit proteins present in our cells that a virus needs for its replication. Our recent work found that proteins targeted by viral proteases represent promising targets for host-targeting antivirals. By identifying and characterizing common targets for viral proteases conserved within and between virus families, we open new avenues to generating broad-acting antivirals to meet the needs of current and future pandemics.