Identification of influenza A nucleoprotein as an antiviral target.
Influenza A remains a significant public health challenge because of the emergence of antigenically shifted or highly virulent strains. Antiviral resistance to available drugs such as adamantanes or neuraminidase inhibitors has appeared rapidly, creating a need for new antiviral targets and new drugs for influenza virus infections. Using forward chemical genetics, we have identified influenza A nucleoprotein (NP) as a druggable target and found a small-molecule compound, nucleozin, that triggers the aggregation of NP and inhibits its nuclear accumulation. Nucleozin impeded influenza A virus replication in vitro with a nanomolar median effective concentration (EC(50)) and protected mice challenged with lethal doses of avian influenza A H5N1. Our results demonstrate that viral NP is a valid target for the development of small-molecule therapies.
Kao
Richard Y
RY
Department of Microbiology, The University of Hong Kong, Hong Kong. rytkao@hkucc.hku.hk
Yang
Dan
D
Lau
Lai-Shan
LS
Tsui
Wayne H W
WH
Hu
Lihong
L
Dai
Jun
J
Chan
Mei-Po
MP
Chan
Che-Man
CM
Wang
Pui
P
Zheng
Bo-Jian
BJ
Sun
Jian
J
Huang
Jian-Dong
JD
Madar
Jason
J
Chen
Guanhua
G
Chen
Honglin
H
Guan
Yi
Y
Yuen
Kwok-Yung
KY
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects; D009980:Influenza A virus / Q000737:chemistry* / Q000187:drug effects*; D007251:Influenza, Human / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D009698:Nucleoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009976:Orthomyxoviridae Infections / Q000821:virology; D020836:Protein Structure, Quaternary; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000998:Antiviral Agents; D009698:Nucleoproteins; D054852:Small Molecule Libraries; D014764:Viral Proteins