Current tools for norovirus drug discovery

Weerasekara, Sahani; Prior, Allan M.; Hua, Duy H.

doi:10.1080/17460441.2016.1178231

Cited by 11 publications

(12 citation statements)

References 115 publications

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“…Antiviral approaches involving direct-acting antiviral agents remain at early stages of preclinical research and mainly target two viral proteins: the protease and the RNA polymerase (Kaufman et al, 2014;Weerasekara et al, 2016). The following sections of this review focus on the structure, function, and small-molecule inhibition of norovirus polymerase.…”

Section: Small Moleculesmentioning

confidence: 99%

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

Deval¹,

Zhang²,

Chuang

et al. 2017

Virus Research

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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.

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Section: Small Moleculesmentioning

confidence: 99%

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

Deval¹,

Zhang²,

Chuang

et al. 2017

Virus Research

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“…The problem is further exacerbated by the current lack of diagnostics and norovirus-specific therapeutics and prophylactics, or vaccines. Thus, there is an urgent and unmet medical need for the discovery and development of anti-norovirus small-molecule therapeutics and prophylactics [11–14], as well as effective vaccines [15–16]. …”

Section: Introductionmentioning

confidence: 99%

“…Both viral and host factors can in principle serve as a launching pad for the discovery of anti-norovirus therapeutics [11–14,17–20]. Prominent viral targets that are particularly well-suited as targets for anti-noroviral drug development include the viral-encoded 3CL protease (3CLpro) and RNA dependent RNA polymerase (RdRp) because of the essential roles they play in viral replication [18].…”

Section: Introductionmentioning

confidence: 99%

“…Prominent viral targets that are particularly well-suited as targets for anti-noroviral drug development include the viral-encoded 3CL protease (3CLpro) and RNA dependent RNA polymerase (RdRp) because of the essential roles they play in viral replication [18]. Following translation of the viral genome, the viral polyprotein is cleaved by 3CLpro, a cysteine protease with a prototypical catalytic triad (Cys 139, His30, Glu54) and a strong preference for a P 1 Gln (or Glu) residue [21], to generate structural and nonstructural proteins [22–24] Norovirus 3CLpro has been the focus of intense investigations and an array of inhibitors of 3CLpro that display anti-norovirus activity have been reported [11–14,19], including peptidyl [25–26] and macrocyclic [27–28] transition state inhibitors and transition state mimics [29]. Importantly, in vivo proof of concept in a mouse model using a dipeptidyl transition state inhibitor of norovirus 3CLpro has also been demonstrated [25].…”

Section: Introductionmentioning

confidence: 99%

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Structure-based exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design of potent and permeable inhibitors

Kankanamalage

Kim

Rathnayake

et al. 2017

European Journal of Medicinal Chemistry

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Human noroviruses are the primary cause of epidemic and sporadic acute gastroenteritis. The worldwide high morbidity and mortality associated with norovirus infections, particularly among the elderly, immunocompromised patients and children, constitute a serious public health concern. There are currently no approved human vaccines or norovirus-specific small-molecule therapeutics or prophylactics. Norovirus 3CL protease has recently emerged as a potential therapeutic target for the development of anti-norovirus agents. We hypothesized that the S4 subsite of the enzyme may provide an effective means of designing potent and cell permeable inhibitors of the enzyme. We report herein the structure-guided exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design and synthesis of effective inhibitors of the protease.

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“…Antiviral compounds screened against caliciviruses so far have mostly involved in vitro enzyme and in vitro cell based models, notably murine norovirus (MNV), the human GI replicon [18], and to a lesser extent FCV, RHDV, rabbit calicivirus and porcine sapovirus (PSaV) [19,20,21,22,23]. These compounds are broadly divided into host-targeting agents and direct-acting antivirals (DAAs), with the latter targeting virus-encoded proteins essential for infection and replication, including the viral protease and RNA-dependent RNA polymerase (RdRp) [24]. Inhibitors of the RdRp are further divided into nucleoside analogues (NAs) and non-nucleoside inhibitors (NNIs) [2].…”

Section: Introductionmentioning

confidence: 99%

The Adenosine Analogue NITD008 has Potent Antiviral Activity against Human and Animal Caliciviruses

Tuipulotu

Fumian

Netzler

et al. 2019

Viruses

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The widespread nature of calicivirus infections globally has a substantial impact on the health and well-being of humans and animals alike. Currently, the only vaccines approved against caliciviruses are for feline and rabbit-specific members of this group, and thus there is a growing effort towards the development of broad-spectrum antivirals for calicivirus infections. In this study, we evaluated the antiviral activity of the adenosine analogue NITD008 in vitro using three calicivirus model systems namely; feline calicivirus (FCV), murine norovirus (MNV), and the human norovirus replicon. We show that the nucleoside analogue (NA), NITD008, has limited toxicity and inhibits calicivirus replication in all three model systems with EC50 values of 0.94 μM, 0.91 µM, and 0.21 µM for MNV, FCV, and the Norwalk replicon, respectively. NITD008 has a similar level of potency to the most well-studied NA 2′-C-methylcytidine in vitro. Significantly, we also show that continual NITD008 treatment effectively cleared the Norwalk replicon from cells and treatment with 5 µM NITD008 was sufficient to completely prevent rebound. Given the potency displayed by NITD008 against several caliciviruses, we propose that this compound should be interrogated further to assess its effectiveness in vivo. In summary, we have added a potent NA to the current suite of antiviral compounds and provide a NA scaffold that could be further modified for therapeutic use against calicivirus infections.

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Current tools for norovirus drug discovery

Cited by 11 publications

References 115 publications

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

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

Structure-based exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design of potent and permeable inhibitors

The Adenosine Analogue NITD008 has Potent Antiviral Activity against Human and Animal Caliciviruses

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