Uncovering cellular substrates of 3C-like proteases to identify conserved virus-host interactions as antiviral targets
Lead Research Organisation:
University of Liverpool
Department Name: Biochemistry & Systems Biology
Abstract
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.
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.
Technical Summary
Positive-sense RNA viruses include the causative agents behind some of the major pathogens impacting society today: SARS-CoV-2, norovirus, and polio. All these viruses express a 3C or 3C-like protease, which is the focus of this proposal. We understand these proteases are crucial for virus replication and cleavage of viral proteins. Still, we do not know which cellular substrates are cleaved as part of a viral strategy to manipulate infected cells.
In brief, our aims are:
- Complete a systematic identification of cellular substrates of viral 3C-like proteases encoded by the three major RNA virus families that cause human disease.
- Evaluate how essential these cellular substrates and substrate cleavage are for productive norovirus and SARS-CoV-2 replication.
- For this subset, develop a mechanistic understanding of how proteolytic cleavage of these cellular substrates subverts their functions in both health and disease.
Our prior data on SARS-CoV-2 already identified 14 wholly novel cellular substrates in SARS-CoV-2 infection alone. Our data underlined the vital importance of these interactions for productive viral infection and how little we know about the canonical function of many of these proteins. The controlled, comparative studies I propose will identify further novel fundamental biology in these crucially important virus-host interactions, and may lay a path to developing host-targeting antivirals.
In brief, our aims are:
- Complete a systematic identification of cellular substrates of viral 3C-like proteases encoded by the three major RNA virus families that cause human disease.
- Evaluate how essential these cellular substrates and substrate cleavage are for productive norovirus and SARS-CoV-2 replication.
- For this subset, develop a mechanistic understanding of how proteolytic cleavage of these cellular substrates subverts their functions in both health and disease.
Our prior data on SARS-CoV-2 already identified 14 wholly novel cellular substrates in SARS-CoV-2 infection alone. Our data underlined the vital importance of these interactions for productive viral infection and how little we know about the canonical function of many of these proteins. The controlled, comparative studies I propose will identify further novel fundamental biology in these crucially important virus-host interactions, and may lay a path to developing host-targeting antivirals.
Organisations
People |
ORCID iD |
| Edward Emmott (Principal Investigator) | |
| Philip Brownridge (Researcher) |