C646, a Novel p300/CREB-Binding Protein-Specific Inhibitor of Histone Acetyltransferase, Attenuates Influenza A Virus Infection

Dongming Zhao; Satoshi Fukuyama; Yuko Sakai-Tagawa; Emi Takashita; Jason E Shoemaker; Yoshihiro Kawaoka

doi:10.1128/AAC.02055-15

C646, a Novel p300/CREB-Binding Protein-Specific Inhibitor of Histone Acetyltransferase, Attenuates Influenza A Virus Infection

Antimicrob Agents Chemother. 2015 Dec 28;60(3):1902-6. doi: 10.1128/AAC.02055-15.

Authors

Dongming Zhao¹, Satoshi Fukuyama¹, Yuko Sakai-Tagawa², Emi Takashita³, Jason E Shoemaker¹, Yoshihiro Kawaoka⁴

Affiliations

¹ Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan.
² Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan.
³ Influenza Virus Research Center, National Institute of Infectious Diseases, Musashimurayama, Tokyo, Japan.
⁴ Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan kawaoka@ims.u-tokyo.ac.jp.

Abstract

New strategies to develop novel broad-spectrum antiviral drugs against influenza virus infections are needed due to the emergence of antigenic variants and drug-resistant viruses. Here, we evaluated C646, a novel p300/CREB-binding protein-specific inhibitor of histone acetyltransferase (HAT), as an anti-influenza virus agent in vitro and in vivo and explored how C646 affects the viral life cycle and host response. Our studies highlight the value of targeting HAT activity for anti-influenza drug development.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiviral Agents / pharmacology*
Benzoates / pharmacology*
CREB-Binding Protein / antagonists & inhibitors*
CREB-Binding Protein / metabolism
Cell Line
Dogs
E1A-Associated p300 Protein / antagonists & inhibitors*
E1A-Associated p300 Protein / metabolism
HEK293 Cells
Histone Acetyltransferases / antagonists & inhibitors*
Humans
Influenza A virus / drug effects*
Madin Darby Canine Kidney Cells
Mice
Mice, Inbred BALB C
Nitrobenzenes
Orthomyxoviridae Infections / drug therapy*
Pyrazoles / pharmacology*
Pyrazolones

Substances

4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid
Antiviral Agents
Benzoates
Nitrobenzenes
Pyrazoles
Pyrazolones
CREB-Binding Protein
E1A-Associated p300 Protein
Histone Acetyltransferases

Grants and funding

This work was supported by the Japan Initiative for Global Research Network on Infectious Diseases from the Ministry of Education, Culture, Sports, Science and Technology, Japan, by grants-in-aid from the Ministry of Health, Labour and Welfare, Japan, by ERATO, by grants from the Strategic Basic Research Program of the Japan Science and Technology Agency, and by the Advanced Research & Development Programs for Medical Innovation from the Japan Agency for Medical Research and Development (AMED).