Biostructural Models for the Binding of Nucleoside Analogs to SARS-CoV-2 RNA-Dependent RNA Polymerase

SARS-CoV-2 is a positive-sense RNA virus that requires an RNA-dependent RNA polymerase (RdRp) for replication of its viral genome. Nucleoside analogs such as Remdesivir and β-d-N⁴-hydroxycytidine are antiviral candidates and may function as chain terminators or induce viral mutations, thus impairing RdRp function. Recently disclosed Cryo-EM structures of apo, RNA-bound, and inhibitor-bound SARS-CoV-2 RdRp provided insight into the inhibitor-bound structure by capturing the enzyme with its reaction product: Remdesivir covalently bound to the RNA primer strand. To gain a structural understanding of the binding of this and several other nucleoside analogs in the precatalytic state, molecular models were developed that predict the noncovalent interactions to a complex of SARS-CoV-2 RdRp, RNA, and catalytic metal cations. MM-GBSA evaluation of these interactions is consistent with resistance-conferring mutations and existing structure-activity relationship (SAR) data. Therefore, this approach may yield insights into antiviral mechanisms and guide the development of experimental drugs for COVID-19 treatment.