Biophysical Society of Canada (BSC)
Société de Biophysique du Canada (SBC)
Kenneth K.S. NG
University of Calgary
Protein Crystallography and Antiviral Drug Design
A wide range of viruses are responsible for medically and economically important diseases in plants and animals. The positive-strand RNA viruses constitute a evolutionarily related group of organisms, including the pathogens responsible for polio, hepatitis A, C and D, viral gastroenteritis (Norwalk Virus), viral meningitis (West Nile Virus) and Severe Acute Respiratory Syndrome (SARS Coronavirus). Novel antiviral drug treatments are urgently needed for most of these diseases, because existing or alternative therapeutic approaches are not effective. Our approach to the development of novel antiviral drug treatments is through the structural analysis of viral proteins using X-ray crystallography. By obtaining structures of viral proteins and their complexes with substrates or binding partners at nearly atomic resolution, it is possible to infer many of their important chemical and biological functions. Understanding the structure and mechanism of viral proteins in turn allows for the design and synthesis of novel chemical molecules that bind to the protein and interfere with a function of the protein that is important for the life cycle of the virus. If effective in a biological setting, these compounds can be considered candidate antiviral drugs. Crystallographic analysis of complexes formed between viral proteins and these novel, designed chemical compounds allows for the refinement and further improvement of the design of second-generation compounds, and further iterations of this cycle of design, synthesis and analysis hopefully leads to the production of therapeutically effective antiviral drugs. Current work on the Norwalk Virus polymerase will be discussed in relation to this overall scheme.