3ATW

Structure-Based Design, Synthesis, Evaluation of Peptide-mimetic SARS 3CL Protease Inhibitors

Summary for 3ATW

• Entry DOI: 10.2210/pdb3atw/pdb
• Related PRD ID: PRD_000815
• Descriptor: 3C-Like Proteinase, peptide ACE-THR-VAL-ALC-HIS-H (3 entities in total)
• Functional Keywords: hydrase proteinase converting, designed inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: SARS coronavirus (SARS-CoV); More
• Cellular location: Non-structural protein 3: Host membrane ; Multi-pass membrane protein . Non-structural protein 4: Host membrane ; Multi-pass membrane protein . Non-structural protein 6: Host membrane ; Multi-pass membrane protein . Non-structural protein 7: Host cytoplasm, host perinuclear region . Non-structural protein 8: Host cytoplasm, host perinuclear region . Non-structural protein 9: Host cytoplasm, host perinuclear region . Non-structural protein 10: Host cytoplasm, host perinuclear region : P0C6U8
• Total number of polymer chains: 4
• Total formula weight: 68704.52

Authors

Akaji, K.,Konno, H.,Mitsui, H.,Teruya, K.,Hattori, Y.,Ozaki, T.,Kusunoki, M.,Sanjho, A. (deposition date: 2011-01-20, release date: 2011-12-14, Last modification date: 2023-11-15)

Primary citation

Akaji, K.,Konno, H.,Mitsui, H.,Teruya, K.,Shimamoto, Y.,Hattori, Y.,Ozaki, T.,Kusunoki, M.,Sanjoh, A.
Structure-Based Design, Synthesis, and Evaluation of Peptide-Mimetic SARS 3CL Protease Inhibitors.
J.Med.Chem., 54:7962-7973, 2011

PubMed Abstract: 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.

PubMed: 22014094
DOI: 10.1021/jm200870n

Experimental method

X-RAY DIFFRACTION (2.36 Å)