A Novel Small Molecule Inhibitor of Influenza A Viruses that Targets Polymerase Function and Indirectly Induces Interferon
Mila Brum Ortigoza1, et al. (2012) PLoS Pathog. 8(4): e1002668.

Speaker: Wei-Jheng Hunag (黃偉政)                                      Time: 15:00~16:00, Dec.12, 2012

Commentator: Dr. Guey-Chuen Perng (彭貴春 老師)          Place: Room 601

Abstract

According to the World Health Organization, influenza viruses cause 3-5 million severe clinical infections and 250,000 to 500,000 deaths annually around the globe. There are three categories of influenza viruses known as types A, B and C. Only type A causes pandemics and thus is the most widely studied. As a result of the typically low fidelity of their RNA-dependent RNA polymerase (RdRp), influenza viruses are frequently mutating and rapidly developing resistance against available anti-viral drugs. Therefore, there is an urgent need to develop new agents for the treatment of influenza. Interferon (IFN) is an essential mediator of the innate immune response and influenza viruses have evolved strategies to evade this response, resulting in increased replication and enhanced pathogenicity. In this study, the authors developed a cell-based high-throughput screening for the identification of small molecules which can restore the IFN production in the presence of influenza A virus infection. Through this screening, they found that compound ASN2 is a potent inhibitor of influenza A viruses. In vitro studies showed that ASN2 preferentially inhibits several seasonal and pandemic influenza A strains and avian H5N1 virus. Furthermore, they showed that ASN2 displays in vivo antiviral activity. Mechanistic studies indicated that ASN2 directly targets to PB1 subunit of the viral RdRp of influenza A virus and indirectly results in inhibition of virus replication and NS1 expression.

Reference

1.          Mahmoudian, S., Auerochs, S., Grone, M., and Marschall, M. (2009). Influenza A virus proteins PB1 and NS1 are subject to functionally important phosphorylation by protein kinase C. J Gen Virol 90, 1392-1397.

2.          Perez, D.R., and Donis, R.O. (2001). Functional analysis of PA binding by influenza a virus PB1: effects on polymerase activity and viral infectivity. J Virol 75, 8127-8136.