Closing the door on flaviviruses: Entry as a target for antiviral drug design

Perera, Rushika; Khaliq, Mansoora; Kühn, Richard

doi:10.1016/j.antiviral.2008.05.004

Cited by 116 publications

(104 citation statements)

References 159 publications

(196 reference statements)

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“…It is interesting to note that non-conservative amino acid substitutions were observed in domain III of the E protein, distinguishing the Brazilian isolates belonging to different lineages. This domain is an immunoglobulin-like domain that plays important roles in flavivirus attachment and antibody neutralization [40,41]. The 12 cysteine residues involved in formation of disulfide bridges as well as two asparagine residues located at positions 67 and 153 of the envelope protein of all isolates were conserved, reinforcing the importance of these amino acids in the envelope protein structure.…”

Section: Discussionmentioning

confidence: 95%

Population dynamics of DENV-1 genotype V in Brazil is characterized by co-circulation and strain/lineage replacement

et al. 2012

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Section: Discussionmentioning

confidence: 95%

Population dynamics of DENV-1 genotype V in Brazil is characterized by co-circulation and strain/lineage replacement

et al. 2012

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“…In contrast to the "spiky" appearance of immature virions, mature virus particles released from cells are relatively smooth. The 180 copies of E protein on mature virions exist as antiparallel dimers that lay flat against the surface of the virus particle (16). Several lines of evidence indicate that the virion maturation process may be quite inefficient, resulting in the generation of infectious partially mature virus particles with structural features of both mature and immature virions (reviewed in reference 14).…”

mentioning

confidence: 99%

Mechanism and Significance of Cell Type-Dependent Neutralization of Flaviviruses

Mukherjee

Dowd

Manhart

et al. 2014

J Virol

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The production of neutralizing antibodies (NAbs) is a correlate of protection for many human vaccines, including currently licensed vaccines against flaviviruses. NAbs are typically measured using a plaque reduction neutralization test (PRNT). Despite its extensive use, parameters that impact the performance of the PRNT have not been investigated from a mechanistic perspective. The results of a recent phase IIb clinical trial of a tetravalent dengue virus (DENV) vaccine suggest that NAbs, as measured using a PRNT performed with Vero cells, do not correlate with protection. This surprising finding highlights the importance of understanding how well the PRNT captures the complexity of the NAb response to DENV. In this study, we demonstrated that the structural heterogeneity of flaviviruses arising from inefficient virion maturation impacts the results of neutralization assays in a cell type-dependent manner. Neutralization titers of several monoclonal antibodies were significantly reduced when assayed on Vero cells compared to Raji cells expressing DC-SIGNR. This pattern can be explained by differences in the efficiency with which partially mature flaviviruses attach to each cell type, rather than a differential capacity of antibody to block infection. Vero cells are poorly permissive to the fraction of virions that are most sensitive to neutralization. Analysis of sera from recipients of live-attenuated monovalent DENV vaccine candidates revealed a strong correlation between the sensitivity of serum antibodies to the maturation state of DENV and cell type-dependent patterns of neutralization. Cross-reactive patterns of neutralization may be underrepresented by the "gold-standard" PRNT that employs Vero cells. IMPORTANCECell type-dependent patterns of neutralization describe a differential capacity of antibodies to inhibit virus infection when assayed on multiple cellular substrates. In this study, we established a link between antibodies that neutralize infection in a cell type-dependent fashion and those sensitive to the maturation state of the flavivirus virion. We demonstrated that cell type-dependent neutralization reflects a differential capacity to measure neutralization of viruses that are incompletely mature. Partially mature virions that most efficiently bind maturation state-sensitive antibodies are poorly represented by assays typically used in support of flavivirus vaccine development. The selection of cellular substrate for neutralization assays may significantly impact evaluation of the neutralization potency of the polyclonal response. These data suggest that current assays do not adequately capture the full complexity of the neutralizing antibody response and may hinder the identification of correlates of protection following flavivirus vaccination.

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“…6 Penelitian tersebut umumnya menitik-beratkan pada proses masuknya protein virus ke dalam sel, replikasi, perakitan, dan pematangan, sehingga diketahui tahapan penting perakitan virus yang dapat dijadikan sebagai target obat. [7][8][9][10] Beberapa protein DENV yang memiliki potensi untuk dijadikan target obat ada-lah glikoprotein envelope (E), 7 protein NS3 yang berfungsi sebagai helikase, 8 dan protein NS5 yang memiliki dua fungsi sebagai metiltransferase 9 serta RNAdependent RNA polymerase. 10 DENV adalah anggota dari keluarga Flaviviridae dan dikelompokkan dalam genus flavivirus dengan genom yang terdiri atas RNA positive-sense berukuran ~ 11kb.…”

Section: Pendahuluanunclassified

Struktur Proteomik Virus Dengue Dan Manfaatnya Sebagai Target Antivirus

Rachmayanti¹

2015

MKA

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AbstrakVirus dengue (DENV) telah menyebabkan sekitar 50 juta kasus infeksi demam berdarah setiap tahunnya, akan tetapi hingga saat ini belum terdapat vaksin maupun antivirus yang mampu mencegah atau mengobati penyakit tersebut. Selama pengembangan vaksin dan antivirus, diperoleh berbagai informasi tentang struktur protein DENV yang dapat dimanfaatkan sebagai target obat. Makalah membahas tentang struktur proteomik pada DENV, yaitu glikoprotein pada envelope, NS3 protease, NS3 helikase, NS5 metiltransferase, dan NS5 RNA-dependent RNA polimerase.

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Closing the door on flaviviruses: Entry as a target for antiviral drug design

Cited by 116 publications

References 159 publications

Population dynamics of DENV-1 genotype V in Brazil is characterized by co-circulation and strain/lineage replacement

Population dynamics of DENV-1 genotype V in Brazil is characterized by co-circulation and strain/lineage replacement

Mechanism and Significance of Cell Type-Dependent Neutralization of Flaviviruses

Struktur Proteomik Virus Dengue Dan Manfaatnya Sebagai Target Antivirus

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