Targeting the Viral Polymerase of Diarrhea-Causing Viruses as a Strategy to Develop a Single Broad-Spectrum Antiviral Therapy

Figures

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  Figure 1. (a) Three-dimensional structure and domains of HNoV RdRp (Norwalk virus, GI.1) in complex with RNA template strand, RNA growing strand and 5-nitrocytidine (PDB ID 3BSN, resolution 1.8 Å); (b) HSaV RdRp (Sapporo virus, Hu/SV/Man/1993/UK) in its apo form (PDB ID 2CKW, resolution 2.3 Å); (c) structural superimposition of the two RdRps.

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  Figure 2. (a) Domains of the HRV VP1 co-crystallised with an RNA fragment and GTP (PDB ID 2R7X, resolution 2.8 Å); (b) colour-coded motifs A-F in the 2R7X crystal structure, with the catalytic residues Asp631 and Asp632 highlighted (part of the conserved GDD sequence).

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  Figure 3. (a) Sequence alignment between HNoV RdRp from the 3BSO crystal structure and HAstV RdRp portion in the Q67726 sequence; (b) final model for HAstV RdRp.

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  Figure 4. (a) Sequence alignment between the bacteriophage f29 DNA polymerase and the polymerase domain of HAdV F serotype 40; (b) final model for the AdV Pol, including the nucleic acid and NTP components minimized from the template.

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  Figure 5. Similarities between RNA and DNA polymerases of diarrhea-causing viruses. (a) Incoming nucleotide binding pocket of the ternary complex of HNoV RdRp co-crystallised with 5-nitro cytidine triphosphate (PDB ID 3BSN); (b) incoming nucleotide binding pocket of the polymerase homology model obtained for HAdV.

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  Figure 6. Structure of reported nucleoside analogues (or pyrophosphate mimics) inhibiting the RdRps of caliciviruses or rotaviruses.

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  Figure 7. Nucleoside analogues inhibiting HAdV pol/HAdV replication.

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  Figure 8. Potential sugar and nucleobase modifications for broad-spectrum nucleoside inhibitors.

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  Figure 9. Predicted binding of one suggested potential broad-spectrum polymerase inhibitor to the HAdV Pol model (a) and to HNoV NTP binding pocket in the 3BSN crystal structure (b).

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  Figure 10. Structures of reported non-nucleoside inhibitors of the Caliciviridae RdRp.