The research project seeks to fill a fundamental gap in our knowledge of how RNA dependent RNA polymerase (RdRp) accurately transcribes the genome of the SARS-CoV-2 virus that has caused the COVID-19 pandemic. The goals of the project are to determine the mechanisms whereby the essential RdRp enzyme and several collaborating partner proteins function in the viral life cycle. The research outcomes will enable better understanding of how current antiviral nucleotide analogs such as Remdesivir inhibit RdRp function, as well as development of new therapeutic strategies against COVID-19 going forward. The project will also support training of two Ph.D. students, both of whom are from underrepresented groups in STEM fields.
Transient state kinetic approaches are planned to interrogate the nucleotide addition reaction catalyzed by SARS-CoV-2 RdRp, nsp12, and the essential cofactors nsp7, nsp8, and nsp14. A central hypothesis to be tested is that the nsp14 exonuclease is essential for increased fidelity of the nsp12 polymerase. To address this hypothesis, the kinetic mechanisms of correct and incorrect nucleotide incorporation catalyzed by nsp12/nsp7/nsp8 complex as well as removal of incorrect nucleotides catalyzed by nsp14 will be determined. The resulting mechanistic knowledge and methods development will better define these proteins as targets for drug discovery.
This RAPID award is made by the Genetic Mechanisms Program in the Division of Molecular and Cellular Biosciences, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
