Feasibility of Known RNA Polymerase Inhibitors as Anti-SARS-CoV-2 Drugs

Figures

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  Figure 1. Phylogenetic analyses and sequence conservation. (a) Phylogenetic analysis was performed by the MEGA X software using the nsp12 sequences of Bat CoV (Black), Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) (Orange), Middle East Respiratory Syndrome Coronavirus (MERS-CoV) (green) and SARS-CoV-2 (blue). The Bat CoV-RaTG13 that was proposed to be the origin of the SARS-CoV-2 is marked in red. The Circos plot was created using Circos software package (v0.69-8). The amino acid changes between consensus SARS-CoV-2 compared to consensus SARS-CoV were identified by multiple sequence alignment and denoted as vertical bars on the Circos plot. (b) The seven conserved RNA-dependent RNA polymerase (RdRp) motifs (A–G) are as denoted by the sequence logo (WebLogo v3). (c) Sequence conservation of SARS-CoV-2 nsp12 motifs are shown as sequence logos (red).

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  Figure 2. Homology-derived molecular model of SARS-CoV-2 nsp12 and the location of conserved RNA polymerase motifs. (a) Overall folding of SARS-CoV-2 nsp12. The fingers, palm and thumb are colored in blue, red and green, respectively. The NiRAN and Interface domains are colored brown and magenta, respectively. (b) The polymerase domain of nsp12. Location of the conserved motifs in SARS-CoV-2 conserved motifs. Motifs A and C, which harbor the catalytic site residues are colored dark-red and red, respectively. Motifs B, D, E, F and G are colored as blue, green, yellow, orange and magenta, respectively.

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  Figure 3. Proposed binding of remdesivir-triphosphate and location of remdesivir resistance residues. (a) Molecular model of nsp12/pt/remdesivir-TP showing the proximity of conserved motifs to the substrate. (b) F483 forms hydrophobic interactions with motif B residues V696 and V640, and (c) position of V560 close to the templating nucleotide.

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  Figure 4. Position of 5-FU resistance mutation in CoV. M618 of SARS-CoV-2 is part of the highly conserved motif A. Note the hydrophobic cluster of residues around M618.

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  Figure 5. Residue positions of two ribavirin resistance mutations (G64 and L420) in poliovirus 3Dpol relative to the active site residue (D328). The backbone of poliovirus 3Dpol is rendered in green ribbon (PDB entry 3OL6 [92]). The equivalent positions in SARS-CoV-2 nsp12 are shown as cyan residues.