Proteolytic processing of the coronavirus replicase polyproteins is essential for ongoing viral RNA synthesis. Therefore, the SARS-CoV proteases are attractive targets for the development of antiviral drugs to reduce viral replication and pathogenicity. The structure and activity of the coronavirus 3CLpro has already been elucidated and the design of inhibitors to 3CLpro as therapeutics has been proposed [9,10]. SARS-CoV 3CLpro has three domains: I (residues 8-101), II (residues 102-184), and III (residues 201-301). Domains I and II, which contain the active site region, are p-barrel domains and III is an a-helical domain. In the active site, a cysteine residue (Cys-145) acts as a nucleophile and a histidine residue (His-41) acts as the general acid base. The X-ray crystal structure of the related enzyme from porcine transmissible gastroenteritis coronavirus (TGEV 3CLpro) and a substrate-analogue hexapeptidyl chloromethyl ketone (CMK) inhibitor 1 (Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK) has been reported . The sequence of this inhibitor was designed based upon P6 and P1 residues of the N-terminal autoprocessing site of TGEV 3CLpro. The corresponding sequences of SARS-CoV 3CLpro and HCoV-229E 3CLpro are Thr-Ser-Ala-Val-Leu and Tyr-Gly-Thr-Leu-Gln, respectively. The binding mode of this hexapeptidyl Gln inhibitor is similar to that which was observed for related human rhinovirus 3C protease (3Cpro) [9,11]. AG7088 (2), a prototype inhibitor of human rhinovirus 3Cpro  appears to bind to this enzyme in an orientation similar to the peptidyl CMK inhibitor in the binding site of TGEV 3CLpro [9,11]. Furthermore, substrate specificity of picornavirus 3Cpro for the P1-, P1'- and P4-sites is very similar to that of coronavirus 3CLpro. As a consequence, compounds 1 and 2 have become starting points for the design of SARS-CoV 3CLpro inhibitors.
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