Maria Agostini

Coronaviruses (CoVs) are widely distributed amongst several species and exhibit great potential for crossing species barriers, as exemplified by the emergence of two novel CoVs, SARS-CoV and MERS-CoV, within the past 15 years. There are no antivirals or vaccines currently available against these infections, demonstrating the need for new therapeutic agents that are broadly effective against CoVs. With a genome of up to 34 kb in length, coronaviruses are the largest of the non-segmented, positive sense, single-stranded RNA viruses. They encode 16 non-structural proteins (nsps) involved in replication. The viral RNA-dependent RNA polymerase (RdRp) encoded within nsp12 is central to viral propagation, as it is required for replication and transcription of the viral genome. Thus, it is an attractive target for antiviral development. GS-5734 and EIDD-1931 are nucleoside analogs that show strong antiviral activity against several viruses, including CoVs. However, the mechanism of action of these antiviral nucleosides in CoVs remains unknown. The goals of this project have been to identify the viral target of the nucleosides as well as assess the ability of EIDD-1931 and GS-5734 to cause mutagenesis and chain termination in CoVs. Together, these studies have helped identify the viral target of the compounds and their effects on viral genome replication. The work contributes to the preclinical development of these promising agents in collaboration with Gilead Sciences and the Emory Institute for Drug Development, and will also aid and inform future antiviral drug design.

Cohort: 2014
Principal Investigator: Mark R. Denison, M.D.
Internship Company: Gilead
Internship Year: 2017
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