1345826-05-2Relevant academic research and scientific papers
Structure-based design, synthesis, and evaluation of peptide-mimetic SARS 3CL protease inhibitors
Akaji, Kenichi,Konno, Hiroyuki,Mitsui, Hironori,Teruya, Kenta,Shimamoto, Yasuhiro,Hattori, Yasunao,Ozaki, Takeshi,Kusunoki, Masami,Sanjoh, Akira
, p. 7962 - 7973 (2011)
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 IC50 value of 98 nM. The resulting compound carried no substrate sequence, except for a P3 site directed toward the outside of the protease. X-ray crystallography provided insights into the protein-ligand interactions.
