Molecular Characterization of the SARS-CoV-2 Helicase and High-Throughput Screening to Identify Small Molecule SARS-CoV-2 Helicase Inhibitors as Anti-Viral Medicines

National Institute On Aging

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Abstract

The COVID-19 Pandemic caused by the novel Severe Acute Respiratory Syndrome (SARS)- Coronavirus (CoV)-2 has necessitated prompt action by biomedical researchers to study key steps in the virus life cycle and identify viral replication targets for molecular interventions leading to therapeutic options. This project focuses on molecular characterization of SARS-CoV-2 (Nsp13) helicase essential for coronavirus replication. Analyses of SARS-CoV-2 helicase will advance our fundamental understanding of its mechanism-of-action and partnership with SARS-CoV-2 Nsp12 RNA-dependent RNA polymerase1. High-throughput screens to identify small molecules that interfere with catalytic functions and interactions of SARS-CoV-2 helicase will provide a strategy for crippling viral replication, a paradigm that builds upon ongoing studies of the Nsp12 polymerase targeting compound Remdesivir2. Discovery of candidate COVID-19 helicase inhibitors may lead to a novel therapeutic anti-viral approach applicable as mono-therapy or combination therapy with anti-viral drugs in use or development. COVID-19 poses a special challenge for the aging population who often have underlying medical conditions3. Age-related comorbid conditions, immuno-senescence, higher risk for infection and sickness in nursing homes, and complications of social distancing for older people likely contribute to elevated risk of mortality for aged individuals. Immune dysfunction and compromised virus (immune) pathogenesis are significant factors influencing the efficacy of future vaccines against COVID-19 for the elderly. Consequently, anti-viral therapies, ultimately combined with immunological strategies, will be advantageous. This COVID-19 research proposal is focused on a key SARS-CoV-2 replication target (helicase) and discovery of small molecule inhibitors as antiviral medicines.