Development of a novel persistent protease inhibitor containing D-amino acid

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Effects of Retro-Inverso(RI) modifications of HTLV-1 protease inhibitors containing ahydroxyethylamine isoster backbone were clarified. Four diastereomers with different configurations at the isoster hydroxyl site and the scissile site substituent were synthesized. Inhibitory activities of the new inhibitors suggest that partially modified RIinhibitors would interact with HTLV-1 protease in the same manner as the parenthydroxyethylamine inhibitor. The design and evaluation of low-molecular weight peptide-based SARS 3CL protease inhibitors are also clarified. Structural optimization was carried out based on X-ray crystallographic analyses of the R188I SARS 3CL protease in a complex with each inhibitor to provide a tetrapeptide aldehyde with an IC50 value of 98 nM. The resulting compound carried no substrate sequence, except for a P3 site directed toward the outside of the protease.