期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 54, 期 23, 页码 7962-7973出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm200870n
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资金
- Japan Society for the Promotion of Science [21590017]
- Grants-in-Aid for Scientific Research [23550195, 21590017, 21689004] Funding Source: KAKEN
The design and evaluation of low molecular weight peptide-based severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CL) protease inhibitors are described. A substrate-based peptide aldehyde was selected as a starting compound, and optimum side-chain structures were determined, based on a comparison of inhibitory activities with Michael type inhibitors. For the efficient screening of peptide aldehydes containing a specific C-terminal residue, a new approach employing thioacetal to aldehyde conversion mediated by N-bromosuccinimide was devised. Structural optimization was carried out based on X-ray crystallographic analyses of the R1881 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 P-3 site directed toward the outside of the protease. X-ray crystallography provided insights into the protein-ligand interactions.
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