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Review
. 2017 Apr 15:234:21-33.
doi: 10.1016/j.virusres.2016.12.018. Epub 2016 Dec 29.

Structure(s), function(s), and inhibition of the RNA-dependent RNA polymerase of noroviruses

Jerome Deval  1 , Zhinan Jin  2 , Ying-Chih Chuang  3 , C Cheng Kao  3
Affiliations
Review

Structure(s), function(s), and inhibition of the RNA-dependent RNA polymerase of noroviruses

Jerome Deval et al. Virus Res. .

Abstract

Noroviruses belong to the Caliciviridae family of single-stranded positive-sense RNA viruses. The genus Norovirus includes seven genogroups (designated GI-GVII), of which GI, GII and GIV infect humans. Human noroviruses are responsible for widespread outbreaks of acute gastroenteritis and represent one of the most common causes of foodborne illness. No vaccine or antiviral treatment options are available for norovirus infection. The RNA-dependent RNA polymerase (RdRp) of noroviruses is a key enzyme responsible for transcription and replication of the viral genome. Here, we review the progress made in understanding the structures and functions of norovirus RdRp and its use as a target for small molecule inhibitors. Crystal structures of the RdRp at different stages of substrate interaction have been determined, which shed light on its multi-step catalytic cycle. The in vitro assays and in vivo animal models that have been developed to identify and characterize inhibitors of norovirus RdRp are also summarized, followed by an update on the current antiviral research targeting different regions of norovirus RdRp. In the future, structure-based drug design and rational optimization of known nucleoside and non-nucleoside inhibitors of norovirus RdRp may pave the way towards the next generation of direct-acting antivirals.

Keywords: Caliciviridae; Non-nucleoside inhibitor; Norovirus; Nucleoside analogs; RNA-dependent RNA polymerase (RdRp); Virus inhibitors.

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Figures

Fig. 1
Fig. 1
Genome organization of the human norovirus. HuNoV genome organization, translation and processing. The VPg linked positive single-stranded RNA genome of HuNoV contains three open reading frames, ORF1, ORF2 and ORF3. The subgenomic RNA only contains ORF2 and ORF3. The ORF1 is translated by host translation machinery into a single polypeptide which then is proteolytically cleaved by the viral protease into six nonstructural proteins, named p48, NTPase, p22, VPg, Protease (Pro), and the RNA dependent RNA polymerase (RdRp). ORF2 and ORF3 are translated into the major and the minor capsid proteins, named VP1 and VP2, respectively. Currently available structures of norovirus proteins are illustrated under each named protein. VP1 PDB: 1IHM, RdRp PDB: 1SH0, protease PDB: 2FYQ.
Fig. 2
Fig. 2
Structure of norovirus polymerase. (A) Schematic of the HuNoV NS7 protein. The fingers, palm and thumb subdomains are colored green, grey and cornflower blue. The motifs are highlighted in distinct colors and the numbers above the motifs denote the amino acid residues that encode the motifs. The structures are based on the structure of the HuNoV complex complexed to the ternary complex and associated with CTP (pdb: 3BSN). (B) Ribbon structures of the NS7 protein. The subdomains are colored green, grey and Motifs A through F are in, respectively, light blue, magenta, grey, and cornflower blue. The motifs and their colors are: A: blue, B: magenta, C: red, D: sky blue, E: green. The front and back views are rotated by 180 °C. (C) A cut-away view of the HuNoV RdRp that illustrates the locations of the template channel, the central channel, and the NTP channel. The locations of motifs are colored as in panel C. (D) Recognition of CTP in the HuNoV ternary complex. Divalent metals, manganese that are coordinated by the active site aspartates are in purple. A water molecule that is used to H-bond to the template RNA is shown as a blue sphere. Only the side chains of amino acids that recognize the CTP are shown.
Fig. 3
Fig. 3
The steps in catalysis of RNA extension by the norovirus RdRp.
Fig. 4
Fig. 4
Mechanism of RNA replication by norovirus RdRp. (A) Norovirus RdRp recognizes the 3′ end of the viral RNA(+) genome (blue), and produces the negative-strand intermediate by de novo initiation of RNA synthesis (red). This RNA serves as template to recruit VPg as primer for synthesis of new RNA(+) copies of viral genomic RNA. Subgenomic RNA is also produced when norovirus RdRp recognizes a promoter sequence present on the downstream of the VP-1 gene on the negative-strand intermediate RNA. (B) Promoter sequence for human norovirus genome.
Fig. 5
Fig. 5
Nucleoside analogs inhibiting norovirus RdRp. (A) Structure and inhibition potency of ribavirin, T-705/Favipiravir, and T-705 ribonucleoside triphosphate analogs T-1106-TP and 2CM-T-1106-TP. (B) Structure and inhibition potency of 2′-C-methyl-cytidine (2-CMC) and 2′-C-methyl-2′-fluroro-cytidine (2′F-2′C-Me-C).
Fig. 6
Fig. 6
Structure of 5-nitro and 2′-amino cytidine triphosphate and their molecular interaction with the HuNoV RdRp. (A) Structure of 5-nitro cytidine triphosphate and interaction with HuNoV RdRp. (B) Structure of 2′-amino cytidine triphosphate and interaction with HuNoV RdRp.
Fig. 7
Fig. 7
Suramin and its analogs as inhibitors of norovirus RdRp. Structure and inhibition potency of suramin, NF023, naphthalene di-sulfonate, and PPNDS.
Fig. 8
Fig. 8
Other non-nucleoside inhibitors of norovirus RdRp. Structure and inhibition potency of NIC02, NIC04, NIC10, and NIC12.
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