A Novel Inhibitor of Dengue Virus Replication That Targets the Capsid Protein

Byrd, Chelsea M.; Dai, Dongcheng; Grosenbach, Douglas W.; Berhanu, Aklile; Jones, Kevin F.; Cardwell, Kara B.; Schneider, Christine A.; Wineinger, Kristin A.; Pagé, Jessica; Harver, Chris; Stavale, Eric; Tyavanagimatt, Shanthakumar; Stone, Melialani A.; Bartenschlager, Ralf; Scaturro, Pietro; Hruby, Dennis E.; Jordan, Robert

doi:10.1128/aac.01429-12

Cited by 137 publications

(108 citation statements)

References 37 publications

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“…This peptide has been suggested to compete with different capsid functions, such as LD association. A recent high-throughput screen identified a small molecule (ST-148) that potently inhibits replication of all four DENV serotypes in vitro by targeting the capsid protein (130). ST-148 has been proposed to enhance capsid self-interaction, likely perturbing viral assembly and disassembly (91).…”

Section: Capsid Protein and Antiviral Strategiesmentioning

confidence: 99%

Properties and Functions of the Dengue Virus Capsid Protein

2016

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Dengue virus affects hundreds of millions of people each year around the world, causing a tremendous social and economic impact on affected countries. The aim of this review is to summarize our current knowledge of the functions, structure, and interactions of the viral capsid protein. The primary role of capsid is to package the viral genome. There are two processes linked to this function: the recruitment of the viral RNA during assembly and the release of the genome during infection. Although particle assembly takes place on endoplasmic reticulum membranes, capsid localizes in nucleoli and lipid droplets. Why capsid accumulates in these locations during infection remains unknown. In this review, we describe available data and discuss new ideas on dengue virus capsid functions and interactions. We believe that a deeper understanding of how the capsid protein works during infection will create opportunities for novel antiviral strategies, which are urgently needed to control dengue virus infections. KeywordsRNA virus; flavivirus; arbovirus; dengue virus; capsid protein; viral encapsidation; viral assembly; lipid droplets DENGUE VIRUSDengue virus (DENV) is the most significant arthropod-borne viral pathogen in humans. The geographical spread and incidence of DENV infections have increased dramatically in recent years. DENV is estimated to cause around 390 million infections per year, placing over 3 billion people at risk of infection (1). In addition to the heavy burden placed on public health, DENV epidemics have a huge economic impact on affected countries.DENV is a member of the Flavivirus genus of the Flaviviridae family (2). The Flavivirus genus includes other important emerging and reemerging human pathogens such as Zika virus (ZIKV), West Nile virus (WNV), Japanese encephalitis virus ( JEV), yellow fever virus (YFV), and Saint Louis encephalitis virus (SLEV) (3). Most flaviviruses are arthropodborne; however, vertebrate-and invertebrate-specific viruses are also members of the group (for a recent review see 4). DENV cycles in nature between Aedes mosquito vectors (mainly DISCLOSURE STATEMENTThe authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptAedes albopictus and Aedes aegypti ) and humans. Four DENV serotypes (DENV1, DENV2, DENV3, and DENV4) circulate in tropical and subtropical regions of the globe (5). They differ from one another by 25-40% at the amino acid level and are further separated into genotypes. Clinical outcomes for all serotypes can be unapparent or result in a spectrum of diseases ranging from self-limited dengue fever to severe dengue, a potentially lethal hemorrhagic illness. The incidence of dengue disease is growing as the mosquito vector spreads owing to urbanization, population growth, international travel, insufficient mosquito control efforts, and global warming.Although vaccines a...

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Section: Capsid Protein and Antiviral Strategiesmentioning

confidence: 99%

Properties and Functions of the Dengue Virus Capsid Protein

2016

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“…This compound is potent against the four dengue virus serotypes, as well as against other flaviviruses; its inhibitor effect was evaluated in in vitro and in vivo assays in mice (AG129), revealing that it significantly reduces viremia and viral loads in vital organs [47]. …”

Section: Capsid Inhibitorsmentioning

confidence: 99%

Inhibitors compounds of the flavivirus replication process

García

Padilla

Castaño

2017

Virol J

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Flaviviruses are small viruses with single-stranded RNA, which include the yellow fever virus, dengue virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, and Zika virus; and are causal agents of the most important emerging diseases that have no available treatment to date. In recent years, the strategy has focused on the development of replication inhibitors of these viruses designed to act mainly by affecting the activity of enzyme proteins, such as NS3 and NS5, which perform important functions in the viral replication process. This article describes the importance of flaviviruses and the development of molecules used as inhibitors of viral replication in this genus.

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“…Within the cytoplasm, the DENV C protein not only is localized to sites of virus assembly, but is found in association with lipid droplets, where it may play an important role in the formation of virus particles (18)(19)(20)(21). The DENV C protein is also localized in the nuclei of infected cells, where it is primarily associated with the nucleolus (22)(23)(24)(25).…”

mentioning

confidence: 96%

Nucleolin Interacts with the Dengue Virus Capsid Protein and Plays a Role in Formation of Infectious Virus Particles

Balinsky

Schmeisser

Ganesan

et al. 2013

J Virol

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Dengue virus (DENV), a member of the genus Flavivirus, causes a spectrum of disease in humans that can range from a mild febrile illness to potentially fatal hemorrhage or shock syndromes. Four serotypes of DENV (DENV-1, -2, -3, and -4) are transmitted by the bite of a mosquito vector and are responsible for more than 50 million infections each year. Infection with one DENV serotype does not confer lasting immunity to the others (1-3). The most severe clinical manifestations of dengue are associated with secondary infections by a heterologous DENV serotype (2). Increasing urbanization, cocirculation of multiple DENV serotypes within the same geographic area, and expansion of its insect vector contribute to the increasing importance of dengue to global health (2, 3).DENV contains a positive-sense single-stranded RNA (ssRNA) genome that is translated as a single open reading frame. The resulting polyprotein is cleaved by virus and host proteases into three structural and at least seven nonstructural proteins (4, 5). The capsid (C) protein functions as a structural component of the DENV virion, encapsulating the ssRNA genome of the virus (4, 5). The DENV C protein is composed of four alpha helices with an unstructured amino terminus and forms antiparallel homodimers.

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A Novel Inhibitor of Dengue Virus Replication That Targets the Capsid Protein

Cited by 137 publications

References 37 publications

Properties and Functions of the Dengue Virus Capsid Protein

Properties and Functions of the Dengue Virus Capsid Protein

Inhibitors compounds of the flavivirus replication process

Nucleolin Interacts with the Dengue Virus Capsid Protein and Plays a Role in Formation of Infectious Virus Particles

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