Development of peptidyl alpha-keto-beta-aldehydes as new inhibitors of cathepsin L--comparisons of potency and selectivity profiles with cathepsin B.
We have utilized previously known substrate and inhibitor specificity profiles for the lysosomal cysteine protease, cathepsin L, to design a new series of putative inhibitors of this enzyme, based on di- and tri-peptidyl alpha-keto-beta-aldehydes. Kinetic evaluation of these compounds revealed Z-Phe-Tyr(OBut)-COCHO, with a Ki 0.6 nM, to be the most potent, synthetic reversible inhibitor of cathepsin L reported to date.
Division of Biomedicinal Chemistry, School of Pharmacy, Queen's University Belfast, Medical Biology Centre, Northern Ireland, UK. j.lynas@qub.ac.uk
J F
JF
Lynas
S J
SJ
Hawthorne
B
B
Walker
D000447:Aldehydes / Q000737:chemistry*; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010450:Endopeptidases; D006801:Humans; D010455:Peptides / Q000737:chemistry*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013379:Substrate Specificity
D000447:Aldehydes; D015853:Cysteine Proteinase Inhibitors; D010455:Peptides; D011994:Recombinant Proteins; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L