Maturation and Structure Based Drug Design of SARS 3CL protease

Severe acute respiratory syndrome (SARS) is an emerging infectious disease caused by a novel human coronavirus. Viral maturation requires a main protease (3CLpro) to cleave the virus-encoded polyproteins. In this study, the dimeric 3-D structure of the C145A mutant protease shows that the active site of one protomer binds with the C-terminal six amino acids of the protomer from another asymmetric unit, mimicking the product-bound form and suggesting a possible mechanism for maturation. This product-bound structure also provides insights into the maturation process of the SARS 3CLpro from the polyprotein and design of new structure-based inhibitors. For structure-based drug design, AG7088 (an anti-rhinivirus drug) is the lead compound for the design of anti-SARS 3CL protease inhibitor. Substrate based bioinformatics, enzyme based, anti-viral cell-based assay and four inhibitor-protease complex crystal structures established a potent anti-SARS protease inhibitor-TG-0205221. Finally, fast, efficient and cost-saving chemical synthesis strategy for structure based anti-viral protease drug design is established.