Crystal structures of murine norovirus-1 RNA-dependent RNA polymerase in complex with 2-thiouridine or ribavirin

Alam, Intekhab; Lee, Jihye; Cho, Ki Joon; Han, Kang Rok; Yang, Jai Sing; Chung, Mi Sook; Kim, Kyung Hyun

doi:10.1016/j.virol.2012.01.016

Cited by 39 publications

(30 citation statements)

References 31 publications

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“…Although in ITC experiments, the K D value of the interaction was in the higher micromolar range (~300 μM), suggesting modest affinity between the molecules, specificity of the interaction is underscored by the absence of interaction between AphB N100E and ribavirin. Much higher K D values (2480 μM to undetectable) were reported for the interactions between viral RNA-dependent RNA polymerases and ribavirin, although some of these enzymes are definitive targets of the drug4950. It is evident from these studies that ribavirin inhibits the function of viral RNA polymerases despite having a low binding affinity for them.…”

Section: Discussionmentioning

confidence: 88%

Ribavirin suppresses bacterial virulence by targeting LysR-type transcriptional regulators

Mandal

Sinha

et al. 2016

Sci Rep

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Targeting bacterial virulence mechanisms without compromising bacterial growth is a promising strategy to prevent drug resistance. LysR-type transcriptional regulators (LTTRs) possess structural conservation across bacterial species and regulate virulence in numerous pathogens, making them attractive targets for antimicrobial agents. We targeted AphB, a Vibrio cholerae LTTR, which regulates the expression of genes encoding cholera toxin and toxin-co-regulated pilus for inhibitor designing. Since AphB ligand is unknown, we followed a molecular fragment-based approach for ligand designing using FDA-approved drugs and subsequent screen to identify molecules that exhibited high-affinity binding to AphB ligand-binding pocket. Among the identified compounds, ribavirin, an anti-viral drug, antagonized AphB functions. Ribavirin perturbed Vibrio cholerae pathogenesis in animal models. The inhibitory effects of the drug was limited to the bacteria expressing wild type AphB, but not its constitutively active mutant (AphBN100E), which represents the ligand-bound state, suggesting that ribavirin binds to the active site of AphB to exert its inhibitory role and there exists no AphB-independent mechanism of its action. Similarly, ribavirin suppressed the functions of Salmonella Typhi LTTR Hrg, indicating its broad spectrum efficacy. Moreover, ribavirin did not affect the bacterial viability in culture. This study cites an example of drug repurposing for anti-infective therapy.

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Section: Discussionmentioning

confidence: 88%

Ribavirin suppresses bacterial virulence by targeting LysR-type transcriptional regulators

Mandal

Sinha

et al. 2016

Sci Rep

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“…The relevance of these approaches to find inhibitors can be questioned. For example while 2TU and ribavirin show a similar binding mode in these crystal structures they differ significantly in their potency to block MNV replication in vitro [85].…”

Section: Ns7-rna-dependent Rna Polymerasementioning

confidence: 90%

“…Surprisingly no primer-template RNA is needed. Also there was no need to use a phosphorylated form of the nucleoside [85]. This explains why the nucleosides tested [5-fluorouracil (5FU), 2-thiouridine (2TU) and ribavirin] bind with some flexibility and/or slightly shifted from the expected conformation.…”

Section: Ns7-rna-dependent Rna Polymerasementioning

confidence: 99%

Norovirus: Targets and tools in antiviral drug discovery

Rocha‐Pereira

Neyts

Jochmans

2014

Biochemical Pharmacology

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The development of antiviral strategies to treat or prevent norovirus infections is a pressing matter. Noroviruses are the number 1 cause of acute gastroenteritis, of foodborne illness, of sporadic gastroenteritis in all age groups and of severe acute gastroenteritis in children less than 5 years old seeking medical assistance [USA/CDC]. In developing countries, noroviruses are linked to significant mortality (~200,000 children <5 years old). Noroviruses are a major culprit for the closure of hospital wards, and associated with increased hospitalization and mortality among the elderly. Transplant patients have significant risk of acquiring persistent norovirus gastroenteritis. Control and prevention strategies are limited to the use of disinfectants and hand sanitizers, whose efficacy is frequently insufficient. Hence, there is an ample need for antiviral treatment and prophylaxis of norovirus infections. The fact that only a handful of inhibitors of norovirus replication have been reported can largely be attributable to the hampering inability to cultivate human noroviruses in cell culture. The Norwalk replicon-bearing cells and the murine norovirus-infected cell lines are the available models to assess in vitro antiviral activity of compounds. Human noroviruses have been shown to replicate (to some extent) in mice, calves, gnotobiotic pigs, and chimpanzees. Infection of interferon-deficient mice with the murine norovirus results in virus-induced diarrhea. Here we review recent developments in understanding which norovirus proteins or host cell factors may serve as targets for inhibition of viral replication. Given the recent advances, significant progress in the search for antiviral strategies against norovirus infections is expected in the upcoming years.

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“…The mechanism of action of nucleoside analogs involves conversion of the inactive nucleosides into their phosphate or diphosphate forms, which are the actual inhibitory species. Consequently, the norovirus RdRp is an attractive target that is well-suited to the development of norovirus-specific therapeutics due to (a) the vital role RdRp plays in the norovirus replication cycle, (b) the availability of high resolution X-ray crystal structures of free and ligand-bound enzyme complexes [72–75] and (c) the absence of a human homolog which diminishes the likelihood of off-target effects. Several novel nucleoside inhibitors have been shown to inhibit norovirus via the inhibition of RdRp (Figure 4) [76–77].…”

Section: Drugs Against Known Targetsmentioning

confidence: 99%

Anti-norovirus therapeutics: a patent review (2010-2015)

Kankanamalage

Weerawarna

Kim

et al. 2016

Expert Opinion on Therapeutic Patents

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Introduction Human noroviruses are the primary causative agents of acute gastroenteritis and are a pressing public health burden worldwide. There are currently no vaccines or small molecule therapeutics available for the treatment or prophylaxis of norovirus infections. An improved understanding of norovirus biology, as well as the pathogenic mechanisms underlying the disease, has provided the impetus for a range of intense exploratory drug discovery efforts targeting viral and host factors. Areas covered An overview of norovirus inhibitors disclosed in the patent literature (2010-present) and Clinicaltrials.gov is presented. The review is further enriched and supplemented by recent literature reports. Expert opinion Seminal discoveries made in recent years, including a better understanding of the pathobiology and life cycle of norovirus, the identification and targeting of multiple viral and host factors, the advent of a replicon system and a small animal model for the preclinical evaluation of lead compounds, and the availability of high resolution X-ray crystal structures that can be utilized in structure-based drug design and lead optimization campaigns, collectively suggest that a small molecule therapeutic and prophylactic for norovirus infection is likely to emerge in the not too distant future.

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Crystal structures of murine norovirus-1 RNA-dependent RNA polymerase in complex with 2-thiouridine or ribavirin

Cited by 39 publications

References 31 publications

Ribavirin suppresses bacterial virulence by targeting LysR-type transcriptional regulators

Ribavirin suppresses bacterial virulence by targeting LysR-type transcriptional regulators

Norovirus: Targets and tools in antiviral drug discovery

Anti-norovirus therapeutics: a patent review (2010-2015)

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