Influenza virus could serve as an extremely effective biowarfare agent. The potentially high virulence of influenza virus was first demonstrated in 1997 in Hong Kong by an avian H5N1 virus that, for people with confirmed H5N1 infections, killed 6 of 18 patients. More serious outbreaks arose in Asia beginning in Fall, 2003. Since January 28, 2004, there have been 20 deaths out of 27 confirmed cases in Vietnam, and 11 deaths out of 16 confirmed cases in Thailand, an extremely high mortality rate. If a similar virus with the ability to spread from human-to-human was effectively utilized in a biowarfare setting, or arose naturally to cause a pandemic, results could be devastating. In a bioterrorist/biowarfare influenza attack, vaccines would likely be of limited initial utility since it takes several months to prepare a vaccine against a new strain, and antigenically different viruses might be used. A more attractive approach is to develop antiviral drugs targeted to essential functions shared by all influenza strains. One such drug target is the neuraminidase (NA). While clinically used drugs that target influenza NA, zanamivir and oseltamivir, are available, our premise is that additional, structurally novel NA inhibitors are needed that (1) are likely to maintain effectiveness for influenza strains resistant to existing NA inhibitors via mutations in the NA active site, and (2) are potentially cheaper to manufacture and stockpile. Such drugs would be useful in both bioterrorism/biowarfare and natural pandemics. We developed the first potent (IC50 = 48 nM) benzoic acid inhibitor of influenza A NA, which is unique as compared to the clinical drugs (3-5 chiral carbons) since it is a chemically simple benzoic acid containing NO chiral carbons. This compound exhibits moderate oral activity in a mouse infection model without toxicity. We now intend to develop new benzoic acids that are more potent NA inhibitors and more efficacious. We also intend to develop at least 1 new, alternative structural class of neuraminidase inhibitor that meets the goals of this application. This we will accomplish by the following specific aims.
Aim 1. Further optimize the inhibitory activity of benzoic acids for influenza A NA.
Aim 2. Identify totally new structural classes of NA inhibitors.
Aim 3. Identify any mutations that arise from passage of the virus in the presence of both our optimized benzoic acids and structurally new inhibitors.
Aim 4. Evaluate whole cell antiviral activity, mammalian cytotoxicity, and in vivo anti-influenza A activity.
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|Li, Yanwu; Silamkoti, Arundutt; Kolavi, Gundurao et al. (2012) Pyrrolidinobenzoic acid inhibitors of influenza virus neuraminidase: the hydrophobic side chain influences type A subtype selectivity. Bioorg Med Chem 20:4582-9|
|Venkatramani, Lalitha; Johnson, Eric S; Kolavi, Gundurao et al. (2012) Crystal structure of a new benzoic acid inhibitor of influenza neuraminidase bound with a new tilt induced by overpacking subsite C6. BMC Struct Biol 12:7|