The main objective of this project is to utilize our extensive preliminary results to design and develop SCLpro inhibitors for therapeutic intervention of Severe Acute Respiratory Syndrome (SARS). Since its first report in Guangdong Province, China, in November, 2002, SARS has spread to other Asian countries, North America and Europe. This epidemic already affected more than 8000 reported individuals by July, 2003, and resulted in 774 deaths. A recently discovered coronavirus has been identified as the etiological agent for SARS. Thus far, no effective therapy exists for this virus. During viral replication, the functional polypeptides are generated from polyproteins by proteolytic processing carried out by a 33.1-kD HCoV 229E main protease that is called 3C-like protease (SCLpro) and the activity of this SCLpro protease is critical to coronavirus replication. Thus, this protease is recognized as an attractive target for drug development for SARS and related infections. In preliminary work, we designed and synthesized a number of SCLpro protease inhibitors based upon the X-ray crystal structure of SCLpro, the X-ray crystal structure of related enzyme of porcine transmissible gastroenteritis (corona)virus (TGEV Mpro) with a substrate-analog hexapeptidyl chloromethyl ketone (CMK) inhibitor, as well as from structural information derived from amodeled inhibitor, AG-7088 in the SCLpro active site. Two of these inhibitors are not only quite active against SARS-SCLpro, but also inhibit MHV (mouse hepatitis virus) and SARS-HCoV cell culture assays at 50 to 100 micromolar concentrations. We have also determined the X-ray structures of these inhibitors complexed with SARS-SCLpro at a resolution of 1.9 Angstroms. This work now forms the basis of our proposed studies in which the power of synthetic medicinal chemistry will be combined with crystallography and molecular modeling and utilized to further develop a new generation of structurally diverse and more potent inhibitors with clinical potential.
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