RAPID: Host-pathogen interactions during genome replication of SARS-CoV2

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Replication of coronaviruses, including SARS-CoV-2 – the causative agent of COVID-19, is expected to involve protein factors from the infected host cell that provide activities not encoded in the viral genome. This project focuses on the need for the virus to co-opt a host 3’ to 5’ RNA helicase to synthesize the negative-strand RNA that serves as template for copying the positive-strand genome. A recent proteomic screen identified a candidate host helicase, DDX10, that interacts with SARS-CoV-2 proteins. The research will employ a suite of experimental approaches to characterize this enzyme and two other host RNA helicases also implicated in SARS-CoV-2 genome replication. Detailed knowledge of how host proteins contribute to viral replication will provide new targets for therapeutic intervention, importantly, in ways that help circumvent drug resistance through viral mutation. The project will also support training of a postdoctoral scholar and development of a new undergraduate biophysics course centered on coronavirus-related topics.Biochemical and biophysical techniques, such as X-ray crystallography, cryo-EM and single molecule spectroscopy, will be applied to determine structure-function properties that govern the helicase mechanism, including polarity, speed, processivity and associated energetics, and how its interactions with the viral NSP7/8 primase influence genome replication. The outcomes are expected to reveal the workings of host proteins during SARS-CoV-2 replication, and thereby open new avenues and novel drug targets to block its proliferation.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.