EFFECTS OF 5′-TRIPHOSPHATE METABOLITES OF SPECIFIC ANTIVIRAL DRUGS ON CTP SYNTHASE ACTIVITY

Abstract

Cytidine-5′-triphosphate (CTP) synthase (CTPS) catalyzes the biosynthesis of CTP from UTP using either L-glutamine or free NH3 as a substrate. CTP is an essential precursor for viral replication; thus, its production has been targeted for the development of antiviral agents. With the advent of SARS-CoV-2, one approach for identifying therapies for COVID-19 is through the repurposing of existing antiviral drugs. To better understand potential off-target effects of repurposed antiviral agents, I analyzed the effects of vidarabine-5′-triphosphate (araATP), ribavirin-5′-triphosphate (RBVNTP), sofosbuvir-5′-triphosphate (STP), and N4-OH-CTP on Escherichia coli CTPS (ecCTPS) activity and filament formation. AraATP and STP were modest substrates for ecCTPS, while RBVNTP and N4-OH-CTP activated and inhibited ecCTPS, respectively. N4-OH-CTP induced filament formation by ecCTPS while STP prevented filament assembly. ATPγS was a substrate for ecCTPS and gemcitabine-5′-triphosphate inhibited both the wild-type and C268A ecCTPS variants to the same extent. Hence, repurposed antiviral drugs could affect intracellular CTP production.