Abstract
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-N 4 -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.
【초록키워드】 COVID-19, Treatment, Structure, SARS-CoV-2, Mutation, Experimental drugs, Antiviral, Remdesivir, RNA, Replication, COVID-19 treatment, nucleoside analog, RdRP, RNA-dependent RNA polymerase, molecular, RNA virus, inhibitor, SAR, Viral mutations, predict, mechanism, nucleoside analogs, cryo-EM structures, binding, SARS-CoV-2 RdRp, Interaction, viral genome, enzyme, complex, candidate, nucleoside, positive-sense RNA virus, approach, provided, induce, catalytic, experimental drug, impairing, RNA primer, 【제목키워드】 SARS-CoV-2, RNA, Model,