Design, Synthesis, and Biological Evaluation of Antiviral Agents Targeting Flavivirus Envelope Proteins

Li, Ze; Khaliq, Mansoora; Zhou, Zhigang; Post, Carol Beth; Kühn, Richard; Cushman, Mark

doi:10.1021/jm800412d

Cited by 93 publications

(49 citation statements)

References 33 publications

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“…The most potent compound, compound 36, contains a chloro-phenyl-thiazole tail (20), which resembles our lead compound (with thiophene replacing thiazole). The mode of binding for the tails of both compounds is therefore expected to be very similar.…”

Section: Compound 6 Acts At An Early Stage During Dengue Virus Infectmentioning

confidence: 95%

A Small-Molecule Dengue Virus Entry Inhibitor

Wang

Patel

Vangrevelinghe

et al. 2009

Antimicrob Agents Chemother

190

140

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The incidence of dengue fever epidemics has increased dramatically over the last few decades. However, no vaccine or antiviral therapies are available. Therefore, the need for safe and effective antiviral drugs has become imperative. The entry of dengue virus into a host cell is mediated by its major envelope (E) protein. The crystal structure of the E protein reveals a hydrophobic pocket that is presumably important for low-pHmediated membrane fusion. High-throughput docking with this hydrophobic pocket was performed, and hits were evaluated in cell-based assays. Compound 6 was identified as one of the inhibitors and had an average 50% effective concentration of 119 nM against dengue virus serotype 2 in a human cell line. Mechanism-ofaction studies demonstrated that compound 6 acts at an early stage during dengue virus infection. It arrests dengue virus in vesicles that colocalize with endocytosed dextran and inhibits NS3 expression. The inhibitors described in this report can serve as molecular probes for the study of the entry of flavivirus into host cells.

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Section: Compound 6 Acts At An Early Stage During Dengue Virus Infectmentioning

confidence: 95%

A Small-Molecule Dengue Virus Entry Inhibitor

Wang

Patel

Vangrevelinghe

et al. 2009

Antimicrob Agents Chemother

190

140

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show abstract

“…The entry of virus into host cells is mediated by the E protein and is the target for neutralizing antibodies that limit viral replication. Several small-molecular inhibitors have been shown to target viral entry [43,44]. Currently, the most advanced targets are the NS2B/NS3 protease and the NS5 RNAdependent RNA polymerase, and several in-silico and highthroughput screens yielding several lead compounds have been reported [45][46][47].…”

Section: Antiviral Drugsmentioning

confidence: 99%

Update on Dengue: Epidemiology, Virus Evolution, Antiviral Drugs, and Vaccine Development

Wilder-Smith

Ooi

Vasudevan

et al. 2010

Curr Infect Dis Rep

185

168

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Dengue virus is the most widespread geographically of the arboviruses and a major public health threat in the tropics and subtropics. Scientific advances in recent years have provided new insights about the pathogenesis of more severe disease and novel approaches into the development of antiviral compounds and dengue vaccines. Phylogenetic studies show an association between specific subtypes (within serotypes) and severity of dengue. The lack of association between maternal antibodies and development of severe dengue in infants in a recent study has called for the rethinking or refinement of the current antibody-dependent enhancement theory of dengue hemorrhagic syndrome in infancy. Such studies should stimulate new directions of research into mechanisms responsible for the development of severe dengue. The life cycle of dengue virus readily shows that virus entry and replication can be targeted by small molecules. Advances in a mouse model (AG 129 mice) have made it easier to test such antiviral compounds. The efforts to find specific dengue inhibitors are intensifying and the tools to evaluate the efficacy of new drugs are now in place for rapid translation into trials in humans. Furthermore, several dengue vaccine candidates are in development, of which the chimeric dengue/yellow fever vaccine has now entered phase 3 trials. Until the availability of a licensed vaccine, disease surveillance and vector population control remain the mainstay of dengue prevention.

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“…This study provides a novel direction for elucidating the mechanism of virus-host interaction. Some proteins have been already used as drug targets in other flaviviruses, such as NS3 helicase, envelope glycoproteins, NS2B-NS3 (serine protease) and NS5 (RNA-directed RNA Polymerase) (Li et al, 2008; Poh et al, 2009; Mayhoub et al, 2011). Therefore, results of our current work should be considered before inhibitor designing.…”

Section: Introductionmentioning

confidence: 99%

Intrinsically Disordered Side of the Zika Virus Proteome

Giri

Kumar

Sharma

et al. 2016

Front. Cell. Infect. Microbiol.

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Over the last few decades, concepts of protein intrinsic disorder have been implicated in different biological processes. Recent studies have suggested that intrinsically disordered proteins (IDPs) provide structural plasticity and functional diversity to viral proteins that are involved in rapid replication and immune evasion in host cells. In case of Zika virus, the roles of protein intrinsic disorder in mechanisms of pathogenesis are not completely understood. In this study, we have analyzed the prevalence of intrinsic disorder in Zika virus proteome (strain MR 766). Our analyses revealed that Zika virus polyprotein is enriched with intrinsically disordered protein regions (IDPRs) and this finding is consistent with previous reports on the involvement of IDPs in shell formation and virulence of the Flaviviridae family. We found abundant IDPRs in Capsid, NS2B, NS3, NS4A, and NS5 proteins that are involved in mature particle formation and replication. In our view, the intrinsic disorder-focused analysis of ZIKV proteins could be important for the development of disorder-based drugs.

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Design, Synthesis, and Biological Evaluation of Antiviral Agents Targeting Flavivirus Envelope Proteins

Cited by 93 publications

References 33 publications

A Small-Molecule Dengue Virus Entry Inhibitor

A Small-Molecule Dengue Virus Entry Inhibitor

Update on Dengue: Epidemiology, Virus Evolution, Antiviral Drugs, and Vaccine Development

Intrinsically Disordered Side of the Zika Virus Proteome

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