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J Phys Chem Lett. 2020 May 11. doi: 10.1021/acs.jpclett.0c00571. [Epub ahead of print]
Novel Coronavirus Polymerase and Nucleotidyl-transferase Structures: Potential to Target New Outbreaks.
Zhang W, Stephen P, Th?riault JF, Wang R, Lin SX.
Abstract
The pandemic outbreak of a new coronavirus (CoV), SARS-CoV-2, has captured the world's attention, demonstrating that CoVs induce a continuous global threat. As this is a highly contagious virus, it is imperative to understand RNA-dependent-RNA-polymerase (RdRp), the key component in virus replication. Although the SARS-CoV-2 genome shares 80% sequence identity with severe acute respiratory syndrome (SARS) CoV, their RdRps and nucleotidyl-transferases (NiRAN) share 98.1% and 93.2% identity, respectively. Sequence alignment of six coronaviruses demonstrated higher identity among their RdRps (60.9-98.1%) and lower identity among their Spike proteins (27-77%). Thus, a 3D structural model of RdRp, NiRAN, nsp7 and nsp8 of SARS-CoV-2 was generated by modelling starting from the SARS counterpart structures. Furthermore, we demonstrate the binding poses of three viral RdRp inhibitors: Galidesivir, Favipiravir, and Penciclovir, which was recently reported to have clinical significance for SARS-CoV-2. The network of interactions established by these drug molecules affirm their efficacy to inhibit viral RNA replication and provide an insight into their structure-based rational optimization for SARS-CoV-2 inhibition.
PMID:32392072DOI:10.1021/acs.jpclett.0c00571