Structure-based design, synthesis, and evaluation of peptide-mimetic SARS 3CL protease inhibitors

Kenichi Akaji, Hiroyuki Konno, Hironori Mitsui, Kenta Teruya, Yasuhiro Shimamoto, Yasunao Hattori, Takeshi Ozaki, Masami Kusunoki, Akira Sanjoh

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80 Citations (Scopus)


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 R188I SARS 3CL protease in a complex with each inhibitor to provide a tetrapeptide aldehyde with an IC 50 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.

Original languageEnglish
Pages (from-to)7962-7973
Number of pages12
JournalJournal of Medicinal Chemistry
Issue number23
Publication statusPublished - 2011 Dec 8


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