Noncovalent tripeptidyl benzyl- and cyclohexyl-amine inhibitors of the cysteine protease caspase-1.
Potent and noncovalent inhibitors of caspase-1 were produced by incorporating a secondary amine (reduced amide) isostere in place of the conventional electrophile (e.g., aldehyde) that normally confers high potency to cysteine protease inhibitors. Benzyl- or cyclohexylamines produced potent, reversible, and competitive inhibitors that were selective for caspase-1 (e.g., K(i) = 47 nM) over caspases 3 and 8 with minimal cytotoxicity. Unlike most cysteine protease inhibitors, these compounds do not react covalently and indiscriminately with thiols.
Löser
Reik
R
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Abbenante
Giovanni
G
Madala
Praveen K
PK
Halili
Maria
M
Le
Giang T
GT
Fairlie
David P
DP
D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001554:Benzene / Q000737:chemistry; D020170:Caspase 1 / Q000737:chemistry / Q000378:metabolism; D061945:Caspase Inhibitors; D002470:Cell Survival / Q000187:drug effects; D003514:Cyclohexylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D017434:Protein Structure, Tertiary
D000588:Amines; D061945:Caspase Inhibitors; D003514:Cyclohexylamines; D015853:Cysteine Proteinase Inhibitors; D020170:Caspase 1; D001554:Benzene