Characterization of a respiratory syncytial virus L protein inhibitor.

Abstract:

:The respiratory syncytial virus (RSV) L protein is a viral RNA-dependent RNA polymerase that contains multiple enzyme activities required for RSV replication. The RSV L inhibitors described in literature are limited by their cytotoxicity or the lack of RSV B subtype coverage. Here, we characterize a new RSV L inhibitor with strong antiviral activity against both RSV A and B subtypes and no detectable cytotoxicity. This compound, AZ-27, was equally active against RSV live viruses and subgenomic replicons and demonstrated advantages over other classes of RSV inhibitors in time-of-addition and cell line dependency studies. Resistance studies identified a dominant mutation in the putative capping enzyme domain of L protein, which conferred strong resistance to the AZ-27 series but not other classes of RSV inhibitors, supporting RSV L protein as the direct target for AZ-27. This novel and broad-spectrum RSV L polymerase inhibitor may pave the way toward an efficacious RSV therapeutic and provide a new tool for interrogation of the L protein function.

authors

Tiong-Yip CL,Aschenbrenner L,Johnson KD,McLaughlin RE,Fan J,Challa S,Xiong H,Yu Q

doi

10.1128/AAC.02540-14

subject

Has Abstract

pub_date

2014-07-01 00:00:00

pages

3867-73

issue

7

eissn

0066-4804

issn

1098-6596

pii

AAC.02540-14

journal_volume

58

pub_type

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