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Review
. 2019 May;39(3):860-886.
doi: 10.1002/med.21545. Epub 2018 Dec 25.

Norovirus antivirals: Where are we now?

Natalie E Netzler  1 , Daniel Enosi Tuipulotu  1 , Peter A White  1
Affiliations
Review

Norovirus antivirals: Where are we now?

Natalie E Netzler et al. Med Res Rev. 2019 May.

Abstract

Human noroviruses inflict a significant health burden on society and are responsible for approximately 699 million infections and over 200 000 estimated deaths worldwide each year. Yet despite significant research efforts, approved vaccines or antivirals to combat this pathogen are still lacking. Safe and effective antivirals are not available, particularly for chronically infected immunocompromised individuals, and for prophylactic applications to protect high-risk and vulnerable populations in outbreak settings. Since the discovery of human norovirus in 1972, the lack of a cell culture system has hindered biological research and antiviral studies for many years. Recent breakthroughs in culturing human norovirus have been encouraging, however, further development and optimization of these novel methodologies are required to facilitate more robust replication levels, that will enable reliable serological and replication studies, as well as advances in antiviral development. In the last few years, considerable progress has been made toward the development of norovirus antivirals, inviting an updated review. This review focuses on potential therapeutics that have been reported since 2010, which were examined across at least two model systems used for studying human norovirus or its enzymes. In addition, we have placed emphasis on antiviral compounds with a defined chemical structure. We include a comprehensive outline of direct-acting antivirals and offer a discussion of host-modulating compounds, a rapidly expanding and promising area of antiviral research.

Keywords: antivirals; direct-acting antivirals; host-targeting drugs; norovirus; therapy.

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Conflict of interest statement

The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic of the human norovirus genome. The norovirus genome is a positive‐sense, single‐stranded RNA genome comprising three ORFs that encode the nonstructural proteins: p48/N‐terminal (NS1/2), NTPase (NS3), p22 (NS4), VPg (NS5), protease (NS6), and RNA polymerase (NS7); and the structural proteins: VP1 and VP2. The numbers at the edges of each domain indicate nucleotide positions. Genome illustration is based on the norovirus GII.4 Sydney 2012 sequence (GenBank accession number JX459908). ORF, open reading frames [Color figure can be viewed at wileyonlinelibrary.com]
Figure 2
Figure 2
Current methods for the identification and characterization of norovirus antivirals. A flow chart depicting the methods and tools available for assessing the effectiveness of norovirus antivirals. Panels in green involve a combination of in silico and in vitro methods. Panels in blue and yellow represent in vitro and in vivo methods, respectively. The purple panel represents clinical testing in human patients. CRFK, Crandell Rees feline kidney; IC50, half maximal inhibitory concentration; qRT‐PCR, quantitative reverse‐transcription polymerase chain reaction; RdRp: RNA‐dependent RNA polymerase; SAR, structure‐activity relationship; TCID50, tissue culture infective dose [Color figure can be viewed at wileyonlinelibrary.com]
Figure 3
Figure 3
The replication cycle and antiviral targets for human norovirus. A, A schematic of the complete norovirus replication cycle is presented and antivirals that have been developed against norovirus are depicted in turquoise circles. The listed compounds represent only those antivirals which have a known target and a more extensive list of antivirals has been described in Table 1. B, A ribbon diagram of the human norovirus GII.4 Sydney 2012 RdRp with fingers (red), thumb (blue), and palm (green) domains color‐coded. The NNI binding sites (Site A, Site B, and the NTP channel) and the NA binding site (active site and Motif C) are labeled. C, A ribbon diagram of the GI.1 Norwalk virus protease (2FYQ) with N‐ and C‐terminal chains colored in magenta and red, respectively. Residues of the catalytic triad are colored in green. Residues for the S2 (cyan) and S4 (yellow) pockets 145 are shown as representative binding sites for protease inhibitors. NTP, nucleoside triphosphate [Color figure can be viewed at wileyonlinelibrary.com]
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