Fellow: Annette Choi

Mentor: Gary Whittaker

DESCRIPTION (provided by applicant): 

Feline coronaviruses (FCoV) can cause one of the deadliest diseases in cat, feline infectious peritonitis (FIP). FIP was historically considered a nearly always fatal disease until the emergence of the antiviral GS-441524 which have been shown to be effective at treating FIP diagnosed cats. GS-441524 is now considered the standard treatment for FIP, despite not being FDA-approved, making its use in the U.S technically illegal. It is known to work as a nucleoside analogue inserting itself into the newly forming viral RNA strand, inhibiting viral replication. However, recent studies with human coronaviruses have shown that GS-441524 can also bind to the viral macrodomain. The viral macrodomain possesses enzymes that counteract the host's antiviral defense system by removing ADP-ribosylation, a post-translational modification that facilitates degradation of viral proteins. This brings up an alternative hypothesis that GS-441524 may have dual antiviral functions: as nucleoside analogue and viral macrodomain inhibitor. In this study, we aim to understand the precise mechanism by which GS-441524 combats FCoV. Additionally, we will assess the potential emergence of GS-441524 resistant FCoV strains, a critical consideration as this antiviral becomes a standard treatment for FIP. Given the possibility of emergence of viral resistance, we also aim to develop novel FCoV antivirals by targeting host cell glutaminase which have been shown in our previous study to be upregulated upon coronavirus infection. Overall, this study will offer significant insights into the functional mechanism of GS-441524 and developing novel antiviral targets for treating FIP.