RAPID: Impact of inhibitors on SARS-CoV-2 polymerase and fidelity control of RNA synthesis

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RNA-dependent RNA polymerase (RdRp) is the core enzyme responsible for replication and transcription in RNA viruses such as SARS-CoV and MERS-CoV. Investigating the mechanism of action of RdRp offers promise for development of new antiviral therapeutics and for understanding the emergence of drug resistance, which is critical for an effective response to the COVID-19 crisis caused by SARS-CoV-2. This project will employ molecular modeling to investigate the structural dynamics underlying RdRp function. Notably, Remdesivir, a nucleotide analog, will be utilized to interrogate RdRp fidelity and better understand how it contributes to viral evolution, as well as the basis for the antiviral activity of this drug. The project also offers training opportunities for graduate and undergraduate students in computational biology.Molecular modeling and all-atom molecular dynamics simulations of conserved SARS-CoV RdRp enzymes are planned to investigate the structural dynamics and energetics governing the nucleotide addition cycle and replication fidelity. The project is guided by specific questions, including how nucleotide analogs impact selection of the correct nucleotide by RdRp, how non-nucleotide inhibitors affect the RdRp mechanism, and what mutations in RdRp might enable drug resistance. The outcomes are expected to yield novel mechanistic information about this important target enzyme for therapeutic intervention. 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.