Aurintricarboxylic acid is a potent inhibitor of influenza A and B virus neuraminidases.
BACKGROUND
Influenza viruses cause serious infections that can be prevented or treated using vaccines or antiviral agents, respectively. While vaccines are effective, they have a number of limitations, and influenza strains resistant to currently available anti-influenza drugs are increasingly isolated. This necessitates the exploration of novel anti-influenza therapies.


RESULTS
We investigated the potential of aurintricarboxylic acid (ATA), a potent inhibitor of nucleic acid processing enzymes, to protect Madin-Darby canine kidney cells from influenza infection. We found, by neutral red assay, that ATA was protective, and by RT-PCR and ELISA, respectively, confirmed that ATA reduced viral replication and release. Furthermore, while pre-treating cells with ATA failed to inhibit viral replication, pre-incubation of virus with ATA effectively reduced viral titers, suggesting that ATA may elicit its inhibitory effects by directly interacting with the virus. Electron microscopy revealed that ATA induced viral aggregation at the cell surface, prompting us to determine if ATA could inhibit neuraminidase. ATA was found to compromise the activities of virus-derived and recombinant neuraminidase. Moreover, an oseltamivir-resistant H1N1 strain with H274Y was also found to be sensitive to ATA. Finally, we observed additive protective value when infected cells were simultaneously treated with ATA and amantadine hydrochloride, an anti-influenza drug that inhibits M2-ion channels of influenza A virus.


CONCLUSIONS
Collectively, these data suggest that ATA is a potent anti-influenza agent by directly inhibiting the neuraminidase and could be a more effective antiviral compound when used in combination with amantadine hydrochloride.
Hashem
Anwar M
AM
Centre for Biologics Research, Biologics and Genetic Therapies Directorate, HPFB, Health Canada, Ottawa, Ontario, Canada; Department of Microbiology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. [corrected].
Flaman
Anathea S
AS
Farnsworth
Aaron
A
Brown
Earl G
EG
Van Domselaar
Gary
G
He
Runtao
R
Li
Xuguang
X
D000547:Amantadine / Q000494:pharmacology; D000818:Animals; D001312:Aurintricarboxylic Acid / Q000494:pharmacology*; D002460:Cell Line; D003470:Culture Media; D019610:Cytoprotection / Q000187:drug effects; D004285:Dogs; D024882:Drug Resistance, Viral / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007181:Inclusion Bodies, Viral / Q000187:drug effects / Q000648:ultrastructure; D009980:Influenza A virus / Q000187:drug effects* / Q000201:enzymology* / Q000502:physiology / Q000648:ultrastructure; D029524:Betainfluenzavirus / Q000187:drug effects* / Q000201:enzymology* / Q000502:physiology / Q000648:ultrastructure; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D053139:Oseltamivir / Q000494:pharmacology; D012367:RNA, Viral / Q000032:analysis; D038301:Virus Inactivation / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D003470:Culture Media; D004791:Enzyme Inhibitors; D012367:RNA, Viral; D053139:Oseltamivir; D001312:Aurintricarboxylic Acid; D000547:Amantadine; D009439:Neuraminidase