On the development of effective drug against severe acute respiratory syndrome (SARS), we focused on the causative corona viral cysteine protease (SARS-CoV 3CLpro), which is essential for its replication, and developed tripeptide-type inhibitors from the native substrate sequences based on two strategies; i) chemical modification at the P1 position (Gln) and ii) introduction of the chemical warhead; an electron-withdrawing arylketone. As a result, Z-Val-Leu-Ala(pyrrolidone-3-yl)-2-thiazole (1 ) exhibited a strong inhibitory activity. According to the molecular modeling study of 1 , it was predicted that there was a large space in the S1' pocket. Therefore, a benzothiazole unit was introduced into the warhead part, resulting in the five-fold increase of the inhibitory activity than 1 . Furthermore, hydrophilic modification of the P4 position, which stuck out from the binding pocket of the protease, was afforded more potent inhibitors than 1 . These inhibitors would be promising lead compounds to develop more potent inhibitors.

Development of tripeptide-type SARS coronavirus 3CL protease inhibitors with an electrophilic 2-benzothiazole ketone structure

244th National Meeting (2012)

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