Small Molecules Targeting the Flavivirus E Protein with Broad-Spectrum Activity and Antiviral Efficacy in Vivo.

Abstract:

:Vaccines and antivirals to combat dengue, Zika, and other flavivirus pathogens present a major, unmet medical need. Vaccine development has been severely challenged by the antigenic diversity of these viruses and the propensity of non-neutralizing, cross-reactive antibodies to facilitate cellular infection and increase disease severity. As an alternative, direct-acting antivirals targeting the flavivirus envelope protein, E, have the potential to act via an analogous mode of action without the risk of antibody-dependent enhancement of infection and disease. We previously discovered that structurally diverse small molecule inhibitors of the dengue virus E protein exhibit varying levels of antiviral activity against other flaviviruses in cell culture. Here, we demonstrate that the broad-spectrum activity of several cyanohydrazones against dengue, Zika, and Japanese encephalitis viruses is due to specific inhibition of E-mediated membrane fusion during viral entry and provide proof of concept for pharmacological inhibition of E as an antiviral strategy in vivo.

journal_name

ACS Infect Dis

journal_title

ACS infectious diseases

authors

Li PC,Jang J,Hsia CY,Groomes PV,Lian W,de Wispelaere M,Pitts JD,Wang J,Kwiatkowski N,Gray NS,Yang PL

doi

10.1021/acsinfecdis.8b00322

subject

Has Abstract

pub_date

2019-03-08 00:00:00

pages

460-472

issue

3

issn

2373-8227

journal_volume

5

pub_type

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