Release of Dengue Virus Genome Induced by a Peptide Inhibitor

Lok, Shee-Mei; Costin, Joshua M.; Hrobowski, Yancey M.; Hoffmann, Andrew R.; Rowe, Dawne K.; Kukkaro, Petra; Holdaway, Heather A.; Chipman, Paul R.; Fontaine, Krystal A.; Holbrook, Michael R.; Garry, Robert F.; Kostyuchenko, V.A.; Wimley, William C.; Isern, Sharon; Rossmann, Michael G.; Michael, Scott F.

doi:10.1371/journal.pone.0050995

Cited by 74 publications

(85 citation statements)

References 35 publications

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“…The release of viral RNAs from viral particles was also assessed by an RNAse digestion assay. Hence, these results suggest that DN59 induces the formation of holes in viral membrane; however, this peptide did not cause the genome release of other RNA enveloped viruses and did not exhibit adverse effect on cell membrane [129].…”

Section: • • Inhibitors Of Membrane Fusion Peptidesmentioning

confidence: 75%

“…[20, 46,49] Sulfated xylomannans Inhibition of virus adsorption and penetration [120] Heteropolysaccharide CrHWE Inhibition of virus adsorption and penetration [120] Chondroitin sulfate E Inhibition of virus adsorption and penetration [21] Curdlan sulfate Inhibition of virus adsorption and penetration [26] Polysaccharide K5 from Escherichia coli Inhibition of virus adsorption and penetration [22] Tannins: chebulagic acid and punicalagin Inhibition of virus adsorption and penetration [122] E hydrophobic pocket target peptides Inhibition of virus adsorption and penetration [123] Doxorubicin derivative: SA-17 Inhibition of virus binding and membrane fusion [124,125] E stem region target peptides Blockade of membrane fusion [126,127] E stem region target peptide: DN59 Release of viral RNAs from viral particles [128,129] E stem region target small molecule:1662G07…”

Section: Carrageenans Inhibition Of Virus Adsorption and Penetrationmentioning

confidence: 99%

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Dengue Virus Entry and Trafficking: Perspectives as Antiviral Target for Prevention and Therapy

2015

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Dengue virus (DENV) is the etiological agent of the most important human viral infection transmitted by mosquitoes in the world. In spite of the serious health threat that dengue represents, at present there are no vaccine or antiviral agents available and treatment of patients consists of supportive therapy. This review will focus on the process of DENV entry into the host cell as a potential target for antiviral therapy. The recent advances in the knowledge of viral and cellular molecules and mechanisms involved in binding, internalization and trafficking of DENV into the host cell until virion uncoating are discussed, together with an overview of the strategies and compounds evaluated for development of antiviral agents targeted to DENV entry. KeywordsDengue is currently the most widespread arbovirosis in the world, with a particularly high prevalence in diverse tropical and subtropical regions of America and Asia [1]. The WHO estimates an occurrence of 50-100 million annual infections, but more recent modelling evaluations increased the number of new possible infections to 390 million per year [2]. There are four serotypes of dengue viruses (DENV), designated DENV-1 to DENV-4, that cocirculate and are transmitted to humans by the bites of the mosquitoes Aedes aegypti and Aedes albopictus. Precisely, the failure in the programs for control of the mosquito vector is one of the reasons for the explosive re-emergence and global spread of dengue in the last few decades in >100 countries, resulting in a serious public health challenge.All serotypes can produce either an inapparent infection or a wide spectrum of clinical outcomes ranging from a mild febrile illness known as dengue fever (DF) to the more severe and life-threatening forms of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) [3]. The initial infection with one DENV serotype leads to lifelong protection against homologous reinfection, but only brief and partial protection against infection with other serotypes. In fact, the secondary infection with a heterologous serotype is considered a risk factor for developing DHF and DSS. These severe clinical manifestations have been associated to the phenomenon known as antibody-dependent enhancement (ADE) [3]. In this process, the antibodies elicited by the primary infection bind to the heterotypic virus without neutralization of viral infectivity, and these immune complexes are opsonized into Fc-receptor positive cells leading to an increase in DENV replication and pathogenesis [4,5].DENV is a member of the genus Flavivirus in the family Flaviviridae. The virion is a small spherical particle, 40-50 nm in diameter, containing a single-stranded positive sense RNA included in an inner nucleocapsid and surrounded by a lipid envelope. The virus genome codes for a single polyprotein that is cleaved into three structural proteins (the capsid protein C,

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Section: • • Inhibitors Of Membrane Fusion Peptidesmentioning

confidence: 75%

Section: Carrageenans Inhibition Of Virus Adsorption and Penetrationmentioning

confidence: 99%

Dengue Virus Entry and Trafficking: Perspectives as Antiviral Target for Prevention and Therapy

2015

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“…Membrane-permeabilizing peptides have many potential applications, including their use as antibacterial, antifungal, and antiviral compounds, 1−5 as anticancer agents, 6,7 as drug delivery enhancers, 8 and as biosensors. 9,10 However, to realize their full potential, we must be able to rationally engineer or modulate their activity and membrane selectivity, objectives which are currently not possible because the mechanism of such peptides cannot yet be described with specific molecular models.…”

Section: Introductionmentioning

confidence: 99%

Conformational Fine-Tuning of Pore-Forming Peptide Potency and Selectivity

et al. 2015

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To better understand the sequence–structure–function relationships that control the activity and selectivity of membrane-permeabilizing peptides, we screened a peptide library, based on the archetypal pore-former melittin, for loss-of-function variants. This was accomplished by assaying library members for failure to cause leakage of entrapped contents from synthetic lipid vesicles at a peptide-to-lipid ratio of 1:20, 10-fold higher than the concentration at which melittin efficiently permeabilizes the same vesicles. Surprisingly, about one-third of the library members are inactive under these conditions. In the negative peptides, two changes of hydrophobic residues to glycine were especially abundant. We show that loss-of-function activity can be completely recapitulated by a single-residue change of the leucine at position 16 to glycine. Unlike the potently cytolytic melittin, the loss-of-function peptides, including the single-site variant, are essentially inactive against phosphatidylcholine vesicles and multiple types of eukaryotic cells. Loss of function is shown to result from a shift in the binding–folding equilibrium away from the active, bound, α-helical state toward the inactive, unbound, random-coil state. Accordingly, the addition of anionic lipids to synthetic lipid vesicles restored binding, α-helical secondary structure, and potent activity of the “negative” peptides. While nontoxic to mammalian cells, the single-site variant has potent bactericidal activity, consistent with the anionic nature of bacterial membranes. The results show that conformational fine-tuning of helical pore-forming peptides is a powerful way to modulate their activity and selectivity.

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“…The membranotropic α 3 and α 4 in DENV4 67 has been studied extensively through mutational studies of the hydrophobic face 60, 61 . Another strategy using peptide mimetic (residues 412 to 444, named DN59) derived from these helices showed inhibition of flaviviruses by releasing genomic RNA 70, 71 . A similar study based on peptide mimetic of residues 419-447 (comprising the conserved stretch following α 3 and α 4) inhibited viral entry 72 .…”

Section: Resultsmentioning

confidence: 99%

“…The Edmundson wheel shows the amphipathic cationic nature of the stem helices. The hydrophobicity of residues in the hydrophobic face is an important determinant of virulence 61, 70, 71 . The conservation of the charged face of α 4 ( c and d ) is in contrast to several differences in the hydrophobic face.…”

Section: Resultsmentioning

confidence: 99%

MEPPitope: spatial, electrostatic and secondary structure perturbations in the post-fusion Dengue virus envelope protein highlights known epitopes and conserved residues in the Zika virus

Chakraborty¹

2016

F1000Res

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The dramatic transformation of the Zika virus (ZIKV) from a relatively unknown virus to a pathogen generating global-wide panic has exposed the dearth of detailed knowledge about this virus. Decades of research in the related Dengue virus (DENV), finally culminating in a vaccine registered for use in endemic regions (CYD-TDV), provides key insights in developing strategies for tackling ZIKV. The previously established MEPP methodology compares two conformations of the same protein and identifies residues with significant spatial and electrostatic perturbations. In the current work, MEPP analyzed the pre-and post-fusion DENV type 2 envelope (E) protein, and identified several known epitopes (His317, Tyr299, Glu26, Arg188, etc.) (MEPPitope). These residues are overwhelmingly conserved in ZIKV and all DENV serotypes. Characterization of α-helices in E-proteins show that α1 is not conserved in the sequence space of ZIKV and DENV. Furthermore, perturbation of α1 in the post-fusion DENV structure includes a known epitope Asp215, a residue absent in the pre-fusion α1. A cationic β-sheet in the GAG-binding domain that is stereochemically equivalent in ZIKV and all DENV serotypes is also highlighted due to a residue pair (Arg286-Arg288) that has a significant electrostatic polarity reversal upon fusion. Finally, two highly conserved residues (Thr32 and Thr40), with little emphasis in existing literature, are found to have significant electrostatic perturbation. Thus, a combination of different computational methods enable the rapid and rational detection of critical residues that can be made the target of small drugs, or as epitopes in the search for an elusive therapy or vaccine that neutralizes multiple members of the Flaviviridae family.

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Release of Dengue Virus Genome Induced by a Peptide Inhibitor

Cited by 74 publications

References 35 publications

Dengue Virus Entry and Trafficking: Perspectives as Antiviral Target for Prevention and Therapy

Dengue Virus Entry and Trafficking: Perspectives as Antiviral Target for Prevention and Therapy

Conformational Fine-Tuning of Pore-Forming Peptide Potency and Selectivity

MEPPitope: spatial, electrostatic and secondary structure perturbations in the post-fusion Dengue virus envelope protein highlights known epitopes and conserved residues in the Zika virus

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