Targeting Norovirus: Strategies for the Discovery of New Antiviral Drugs

Rocha‐Pereira, Joana; Nascimento, María Säo José

doi:10.5772/32677

Cited by 4 publications

(6 citation statements)

References 154 publications

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“…Resistance development is a major obstacle in antiviral therapy, and almost all active antiviral agents have shown to select for resistance mutations. To assess whether resistant variants to compound 6 would easily arise (thus the class of compounds would have a low barrier to resistance) or if many passages (months) and multiple mutations would be required to confer resistance to the compound (high barrier to resistance), we passaged the virus in the presence of compound 6 up to 30 consecutive times [15][16][17][18][19]. The latter indicates a high barrier to resistance similar to 2CMC [14].…”

Section: Discussionmentioning

confidence: 99%

Discovery of a Novel Class of Norovirus Inhibitors with High Barrier of Resistance

et al. 2021

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Human noroviruses (HuNoVs) are the most common cause of viral gastroenteritis resulting in ~219,000 deaths annually and a societal cost of ~USD60 billion. There are no antivirals or vaccines available to treat and/or prevent HuNoV. In this study, we performed a large-scale phenotypical antiviral screening using the mouse norovirus (MNV), which included ~1000 drug-like small molecules from the Drug Design and Synthesis Centre (Sapienza University, Rome). Compound 3‑((3,5-dimethylphenyl)sulfonyl)-5-chloroindole-N-(phenylmethanol-4-yl)-2.carboxamide (compound 1) was identified as an inhibitor of MNV replication with an EC50 of 0.5 ± 0.1 µM. A series of 10 analogs were synthesized of which compound 6 showed an improved potency/selectivity (EC50 0.2 ± 0.1 µM) against MNV; good activity was also observed against the HuNoV GI replicon (EC50 1.2 ± 0.6 µM). Time-of-drug-addition studies revealed that analog 6 acts at a time point that coincides with the onset of viral RNA replication. After six months of selective pressure, two compound 6res variants were independently selected, both harboring one mutation in VPg and three mutations in the RdRp. After reverse engineering S131T and Y154F as single mutations into the MNV backbone, we did not find a markedly compound 6res phenotype. In this study, we present a class of novel norovirus inhibitors with a high barrier to resistance and in vitro antiviral activity.

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Section: Discussionmentioning

confidence: 99%

Discovery of a Novel Class of Norovirus Inhibitors with High Barrier of Resistance

et al. 2021

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“…However, the intestine presents several distinct barriers and, therefore, the design of robust non-viral delivery systems is key to future success. Several non-viral delivery strategies have provided evidence of activity in vivo [ 4 , 5 ]. This report reviews the possibility of siRNA-mediated inhibition of the RNA norovirus genome and the challenges that an oral gastrointestinal-delivery system will face.…”

Section: Discussionmentioning

confidence: 99%

siRNA-mediated targeting of the RNA-dependent RNA polymerase in the Norovirus genome

2015

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“…Noroviruses are small, non-enveloped, single stranded, positive sense RNA viruses of 27 -35 nm in diameter and belong to the genus Norovirus of the family Caliciviridae [9,10,[18][19][20][21]. The family Caliciviridae comprises of four other genera called Sapovirus, Lagovirus, Vesivirus, and Nebovirus, and only the viruses in the Norovirus and Sapovirus genera cause acute gastroenteritis in humans and animals [9,10,19].…”

Section: Biology Of Norovirusesmentioning

confidence: 99%

“…Based on molecular characterization of the major viral capsid VP1 gene, noroviruses are divided into five geno-groups, GI -GV, that share greater than 60% amino acid identity in the VP1 protein [19,22]. Noroviruses that cause gastroenteritis in humans belong to the geno-groups GI, II and IV, which are further subdivided into 26 or more genotypes that share greater than 80% identity in amino acid sequence of VP1 [20]. Viruses in the GII group are more common and GII.4 sub variants are associated with most of the recent major norovirus outbreaks [2,23].…”

Section: Biology Of Norovirusesmentioning

confidence: 99%

Current tools for norovirus drug discovery

Weerasekara

Prior

Hua

2016

Expert Opinion on Drug Discovery

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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.

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Targeting Norovirus: Strategies for the Discovery of New Antiviral Drugs

Cited by 4 publications

References 154 publications

Discovery of a Novel Class of Norovirus Inhibitors with High Barrier of Resistance

Discovery of a Novel Class of Norovirus Inhibitors with High Barrier of Resistance

siRNA-mediated targeting of the RNA-dependent RNA polymerase in the Norovirus genome

Current tools for norovirus drug discovery

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