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Current tools for norovirus drug discovery - PubMed

Review

Current tools for norovirus drug discovery

Sahani Weerasekara et al. Expert Opin Drug Discov. 2016 Jun.

Abstract

Introduction: Rapid transmission of norovirus often occurs due to its low infectious dosage, high genetic diversity and its short incubation time. The viruses cause acute gastroenteritis and may lead to death. Presently, no effective vaccine or selective drugs accepted by the United States Food and Drug Administration (FDA) are available for the treatment of norovirus. Advances in the development of norovirus replicon cell lines, GII.4-Sydney HuNoV strain human B cells, and murine and gnotobiotic pig norovirus models have facilitated the discovery of effective small molecule inhibitors in vitro and in vivo.

Areas covered: This review gives a brief discussion of the biology and replication of norovirus before highlighting the discovery of anti-norovirus molecules. The article coverage includes: an overview of the current state of norovirus drug discovery, the targeting of the norovirus life cycle, the inhibition of structural and nonstructural proteins of norovirus such as proteases and polymerase, and the blockage of virus entry into host cells. Finally, anti-norovirus drugs in the clinical development stage are described.

Expert opinion: The current approach for the counteraction of norovirus focuses on the inhibition of viral RNA polymerase, norovirus 3C-like protease and the structural proteins VP1 as well as the blockade of norovirus entry. Broad-spectrum anti-norovirus molecules, based on the inhibition of 3C-like protease, have been developed. Other host factors and ways to overcome the development of resistance through mutation are also being examined. A dual approach in targeting viral and host factors may lead to an effective counteraction of norovirus infection. Current successes in developing norovirus replicon harboring cells and norovirus infected human cells, as well as murine norovirus models and other animal models such as piglets have facilitated the discovery of effective drugs and helped our understanding of its mechanism of action.

Keywords: 3CLpro; Gastroenteritis; norovirus; polymerase inhibitors; protease inhibitors; proteases; virus entry.

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Conflict of interest statement

Declaration of Interest

The authors are supported by a grant from the National Institutes of Health (U01 AI081891 to DH Hua) and the Johnson Cancer Research Center. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Figures

Figure 1
Figure 1

Organization of human norovirus genome.

Figure 2
Figure 2

Structures of L-fucose-tag, polymer 1, polymer 2, L-fucose, citrate, and four computer generated HBGA inhibitors 1 – 4.

Figure 3
Figure 3

Representative inhibitors against binding of noroviruses to the corresponding HBGA receptors.

Figure 4
Figure 4

Representative peptidyl norovirus protease inhibitors.

Figure 5
Figure 5

Representative chemical structures of RdRp inhibitors 23 – 31, entry blocking inhibitors 32 – 34, and nitazoxanide.

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