STRUCTURES OF INFLUENZA VIRUS PROTEINS. Ming Luo, University of Alabama at Birmingham, 1918 University Blvd., Birmingham, AL 35294

We have determined the structure of type B influenza virus neuraminidase. Influenza virus infection remains to be an uncontrolled human disease which causes up to 20,000 death per year. Novel inhibitors guided by the crystal structure of NA from several virus strains have been developed and structures of NA complexed with various inhibitors are reported here. These compounds (benzoic acid derivatives) are aromatic in nature and offer the advantages of chemical stability and simplicity in chemical synthesis. They also have the potential to be orally active. 13 compounds have thus far been designed and synthesized. The most potent inhibitor synthesized so far has an IC₅₀ value around 2 uM in NA enzyme inhibition assays and was shown to reduce influenza virus HA titer in cell culture by 50% at a concentration between 1 - 10 uM. Since a large number of compounds representing different chemical classes have been prepared, they can be quickly screened when new strains emerge in a pandemic. If they are not effective, we can model the new strain based on existing NA structures and come up with new modifications. Since aromatic compounds are easier in chemical synthesis, this process can be fast.

In addition, we are working on the structure of other influenza proteins which can be potential targets for structure-based drug design. Currently, we have grown crystals of M1 and are in the process of determining the structure. M1 is relatively more conserved when compared with NA. With drugs targeted to different proteins, we have a better chance to handle a pandemic.