Discovery of novel antiviral agents directed against the influenza A virus nucleoprotein using photo-cross-linked chemical arrays.
The nucleoprotein (NP) of the influenza virus is expressed in the early stage of infection and plays important roles in numerous steps of viral replication. NP is relatively well conserved compared with viral surface spike proteins. This study experimentally demonstrates that NP is a novel target for the development of new antiviral drugs against the influenza virus. First, artificial analogs of mycalamide A in a chemical array bound specifically with high affinity to NP. Second, the compounds inhibited multiplication of the influenza virus. Furthermore, surface plasmon resonance imaging experiments demonstrated that the binding activity of each compound to NP correlated with its antiviral activity. Finally, it was shown that these compounds bound NP within the N-terminal 110-amino acid region but their binding abilities were dramatically reduced when the N-terminal 13-amino acid tail was deleted, suggesting that the compounds might bind to this region, which mediates the nuclear transport of NP and its binding to viral RNA. These data suggest that compound binding to the N-terminal 13-amino acid tail region may inhibit viral replication by inhibiting the functions of NP. Collectively, these results strongly suggest that chemical arrays are convenient tools for the screening of viral product inhibitors.
Hagiwara
Kyoji
K
Viral Infectious Diseases Unit, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Kondoh
Yasumitsu
Y
Ueda
Atsushi
A
Yamada
Kazunori
K
Goto
Hideo
H
Watanabe
Toshiki
T
Nakata
Tadashi
T
Osada
Hiroyuki
H
Aida
Yoko
Y
D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D009980:Influenza A virus; D019590:Nucleocapsid Proteins; D055668:Photochemical Processes; D011714:Pyrans / Q000737:chemistry* / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014758:Viral Core Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D011714:Pyrans; D016601:RNA-Binding Proteins; D014758:Viral Core Proteins; C059646:mycalamide A