Novel Molecular Target for Influenza Virus Antiviral Development
Background Influenza A viruses cause a highly contagious respiratory disease in humans that causes a significant loss of life each year, and dramatic mortality rates during human pandemics. H5N1 avian influenza A viruses, so-called bird flus, which have a human mortality rate of approximately 50% since 1997, are prime candidates for the next pandemic influenza A virus. At present H5N1 viruses are not readily transmissible between humans, but it is quite possible that they can acquire such transmissibility via mutations and/or reassortment of genes with circulating human influenza A viruses. The primary means for controlling influenza virus epidemics is vaccination, but antivirals provide an important additional line of defense, particularly for a rapidly-spreading pandemic. Only two classes of influenza virus antivirals are currently available: inhibitors of the viral M2 ion channel protein (amantadine and rimantadine); and inhibitors of the viral neuraminidase (zanamivir and oseltamivir). The emergence of influenza A viruses resistant to the M2 inhibitors occurs at high frequency in treated patients. In addition, resistant to the neuraminidase inhibitors has also been noted in a high percentage of influenza A isolates from treated patients. The emergence of influenza A viruses resistant to these two classes of antiviral drugs highlights the need for additional antiviral drugs against influenza A virus.
Invention Description The influenza virus non-structural protein 1 (NSIA) plays a central role in the virus cellular pathogenicity. NSIA inhibits the processing of cellular messenger RNAs through interactions with two cellular proteins, thereby inhibiting the innate interferon response and leading to preferential translation of virus RNA. When NSIA binding to one of these cellular proteins is blocked, the replication of Influenza is dramatically reduced, producing 35 fold less Influenza than virus grown in control environment. This inhibition is specific to Influenza A; no effect was observed with Influenza B. Inhibition of NSIA binding results to increased interferon production resulting in virus inhibition and effective immune responses. These results indicate that the cellular protein binding site of the NS1A protein is a novel and potent target for the development of small molecule antiviral drugs directed against influenza A virus.
Overcomes existing problems of developing resistance to antivirals
Drugs directed at viral targets different from those of current influenza antivirals
IP Status One U.S. patent application filed
UT Researcher Robert M. Krug, Ph.D., School of Biological Sciences, The University of Texas at Austin Karen Y. Twu, B.S.
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