Characterization of a respiratory syncytial virus L protein inhibitor.
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.
Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
Choi-Lai
CL
Tiong-Yip
Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
Lisa
L
Aschenbrenner
Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
Kenneth D
KD
Johnson
Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
Robert E
RE
McLaughlin
Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
Jun
J
Fan
Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
SreeRupa
S
Challa
Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
Hui
H
Xiong
Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA qin.yu@astrazeneca.com.
Qin
Q
Yu
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003521:Cyclopropanes / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D006801:Humans; D008969:Molecular Sequence Data; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D012093:Replicon / Q000235:genetics; D018357:Respiratory Syncytial Virus Infections / Q000821:virology*; D018113:Respiratory Syncytial Virus, Human / Q000187:drug effects*; D014764:Viral Proteins / Q000037:antagonists & inhibitors*
C500207:6-(4-((biphenyl-2-ylcarbonyl) amino)benzoyl)1-N-cyclopropyl-5,6-dihydro-4H-thieno(3,2-d)(1)benzazepine-2-carboxamide; C000601049:AZ-27 compound; D000998:Antiviral Agents; D001552:Benzazepines; D003521:Cyclopropanes; D014764:Viral Proteins; D009536:Niacinamide; D012324:RNA-Dependent RNA Polymerase