Identification of quinolone derivatives as effective anti-Dengue virus agents.

Abstract:

:Dengue virus (DENV) infection is one of the most important infectious diseases in tropical and subtropical regions around the world. Previously, we performed an initial phenotypic screening of 7000 compounds using DENV type 2 (DENV2)-infected BHK-21 cells to identify small molecules which could inhibit virus replication. In this study, we describe two novel compounds with anti-DENV2 activity, tentatively named Compound-X and Compound-Y. Both compounds possess a quinolone skeleton, and the EC50s of Compound-X and Compound-Y against DENV2 were 3.9 μM and 9.2 μM, respectively. Based on a DENV replicon assay, it was suggested that these compounds have anti-DENV2 activity by inhibition of a step in virus replication. Furthermore, using mutational analysis we obtained compounds-resistant to DENV2 infection and identified a mutation, V130A in the NS5 methyltransferase (MTase) domain. However, these compounds did not inhibit MTase activity. In addition, incorporation of an additional NS1 N246D mutation with the NS5 V130A mutation in DENV2 resulted in recovery of viral replication and a further reduction of the sensitivity to the quinolone compounds by an unknown mechanism. Therefore further investigations are required to clarify the antiviral mechanisms of these quinolone compounds.

journal_name

Antiviral Res

journal_title

Antiviral research

authors

Nobori H,Uemura K,Toba S,Sanaki T,Shishido T,Hall WW,Orba Y,Sawa H,Sato A

doi

10.1016/j.antiviral.2020.104969

subject

Has Abstract

pub_date

2020-12-01 00:00:00

pages

104969

eissn

0166-3542

issn

1872-9096

pii

S0166-3542(20)30383-1

journal_volume

184

pub_type

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