A Small-Molecule Dengue Virus Entry Inhibitor

Wang, Qingyin; Patel, Sonika; Vangrevelinghe, Eric; Xu, Hao; Rao, Ranga; Jaber, Deana; Schul, Wouter; Gu, Feng; Heudi, Olivier; Ling, Ngai; Poh, Mee Kian; Phong, Wai Yee; Keller, Thomas H.; Jacoby, Edgar; Vasudevan, Subhash G.

doi:10.1128/aac.01148-08

Cited by 194 publications

(147 citation statements)

References 38 publications

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“…The cell-based flavivirus immunodetection (CFI) assay was performed as described previously (37). In brief, 2 ϫ 10 4 A549 cells per well in a 96-well plate were infected with DENV-2 (New Guinea C strain) at a multiplicity of infection (MOI) of 0.3 in the presence of 2-fold serial dilutions of the compound.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Dengue Virus by Targeting Viral NS4B Protein

Xie

Wang²,

Xu³

et al. 2011

J Virol

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143

121

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We report a novel inhibitor that selectively suppresses dengue virus (DENV) by targeting viral NS4B protein. Genetic analysis, using DENV-2 replicon and recombinant viruses, demonstrated that each of the two NS4B mutations alone confers partial resistance and double mutations confer additive resistance to the inhibitor in mammalian cells. In addition, we found that a replication defect caused by a lethal NS4B mutation could be partially rescued through trans complementation. The ability to complement NS4B in trans affected drug sensitivity when a single cell was coinfected with drug-sensitive and drug-resistant viruses. Mechanistically, NS4B was previously shown to interact with the viral NS3 helicase domain; one of the two NS4B mutations recovered in our resistance analysis-P104L-abolished the NS3-NS4B interaction (

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Section: Methodsmentioning

confidence: 99%

Inhibition of Dengue Virus by Targeting Viral NS4B Protein

Xie

Wang²,

Xu³

et al. 2011

J Virol

Self Cite

143

121

View full text Add to dashboard Cite

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“…The cell-based flavivirus immunodetection (CFI) assay was performed as described previously (47). Briefly, A549 cells were infected with DENV-2 (strain New Guinea C; multiplicity of infection [MOI] of 0.3) in the presence of 2-fold serial dilutions of compounds.…”

Section: Methodsmentioning

confidence: 99%

“…To validate the antiviral activity, we analyzed the compound using a CFI assay. The CFI assay is an enzyme-linked immunosorbent assay (ELISA)-based assay that measures the amount of envelope protein in cells infected with DENV (47). The compound reduced viral E protein production in a dose-dependent manner, with an estimated EC 50 of 2.4 nM (Fig.…”

Section: Identification Of Nitd-982mentioning

confidence: 99%

Inhibition of Dengue Virus through Suppression of Host Pyrimidine Biosynthesis

Wang

Bushell

Qing

et al. 2011

J Virol

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151

131

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Viral replication relies on the host to supply nucleosides. Host enzymes involved in nucleoside biosynthesis are potential targets for antiviral development. Ribavirin (a known antiviral drug) is such an inhibitor that suppresses guanine biosynthesis; depletion of the intracellular GTP pool was shown to be the major mechanism to inhibit flavivirus. Along similar lines, inhibitors of the pyrimidine biosynthesis pathway could be targeted for potential antiviral development. Here we report on a novel antiviral compound (NITD-982) that inhibits host dihydroorotate dehydrogenase (DHODH), an enzyme required for pyrimidine biosynthesis. The inhibitor was identified through screening 1.8 million compounds using a dengue virus (DENV) infection assay. The compound contains an isoxazole-pyrazole core structure, and it inhibited DENV with a 50% effective concentration (EC 50 ) of 2.4 nM and a 50% cytotoxic concentration (CC 50 ) of >5 M. NITD-982 has a broad antiviral spectrum, inhibiting both flaviviruses and nonflaviviruses with nanomolar EC 90 s. We also show that (i) the compound inhibited the enzymatic activity of recombinant DHODH, (ii) an NITD-982 analogue directly bound to the DHODH protein, (iii) supplementing the culture medium with uridine reversed the compoundmediated antiviral activity, and (iv) DENV type 2 (DENV-2) variants resistant to brequinar (a known DHODH inhibitor) were cross resistant to NITD-982. Collectively, the results demonstrate that the compound inhibits DENV through depleting the intracellular pyrimidine pool. In contrast to the in vitro potency, the compound did not show any efficacy in the DENV-AG129 mouse model. The lack of in vivo efficacy is likely due to the exogenous uptake of pyrimidine from the diet or to a high plasma protein-binding activity of the current compound.

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“…Dengue fever epidemics has increased numerously over the last few decades (Ligon et al 2005) therefore Developing antiviral drug and vaccine is becoming very important due to the global threat of viral disease pandemics (Noble et al 2010;Wang et al 2009). The functional similarity between the NS2B/NS3 proteases from the four genetically and antigenically distinct serotypes was identified by the differences in their substrate specificity using tetrapeptide and octapeptide libraries in a positional scanning format, each containing 130,321 substrates (Guzman et al 2010).…”

Section: Discussionmentioning

confidence: 99%

<i>In silico</i> antigenic site evaluation and antiviral therapy against dengue serotypes

Parida

Deka

Shankar

et al. 2014

Bangladesh J Pharmacol

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Non Structural protein 3 (NS3) constitute protease, helicase and polymerase that are essential for dengue virus replication. The aim of the present study is to block the replication of the virus by targeting the NS3 Protein. The retrieved sequences of NS3 protein from National Centre for Biotechnology information (NCBI) shows that the antigenic sites of the protein are highly variable in all the four serotypes of dengue virus (DENV) i.e. DENV I, DENV II, DENV III and DENV IV. DENV III found to be most distantly related serotype among all the serotypes studied using UPGMA method. The 3D structure of NS3 protein was modeled using homology modeling by MODELLER 9v8. Evaluation of the constructed NS3 protein models were done by PROCHECK, WhatIf using Exome Horizon. The derived compounds of mycophenolic acid and ribavirin were docked as ligands to the constructed models of NS3 protein using Autodock 4.2 for Protein-ligand interaction study.

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A Small-Molecule Dengue Virus Entry Inhibitor

Cited by 194 publications

References 38 publications

Inhibition of Dengue Virus by Targeting Viral NS4B Protein

Inhibition of Dengue Virus by Targeting Viral NS4B Protein

Inhibition of Dengue Virus through Suppression of Host Pyrimidine Biosynthesis

<i>In silico</i> antigenic site evaluation and antiviral therapy against dengue serotypes

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