Aza-peptide epoxides: potent and selective inhibitors of Schistosoma mansoni and pig kidney legumains (asparaginyl endopeptidases).
Aza-peptide epoxides are a new class of irreversible cysteine protease inhibitors. Derivatives containing a P1 aza-asparagine residue are specific for Schistosoma mansoni and pig kidney legumains, which are clan CD cysteine proteases. The inhibitors have second-order rate constants of up to 10(4) M(-1) s(-1) with pig kidney legumain and IC50 values as low as 45 nM with S. mansoni legumain. The most potent epoxides contain an ester moiety with S,S stereochemistry attached to the epoxide. Interestingly, amide and amino acid derivatives of the epoxysuccinate moiety were not inhibitors of legumain, while disubstituted amide derivatives are quite potent. The inhibitors have little or no inhibitory activity with other proteases such as caspases, chymotrypsin, papain, cathepsin B, granzyme B, and various aspartyl proteases.
James
Karen Ellis
KE
School of Chemistry and Biochemistry, and the Petit Institute for Bioscience and Bioengineering, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA.
Götz
Marion G
MG
Caffrey
Conor R
CR
Hansell
Elizabeth
E
Carter
Wendy
W
Barrett
Alan J
AJ
McKerrow
James H
JH
Powers
James C
JC
D000818:Animals; D001372:Aza Compounds / Q000737:chemistry; D003374:Coumarins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D004852:Epoxy Compounds / Q000737:chemistry; D007668:Kidney / Q000737:chemistry / Q000201:enzymology*; D007700:Kinetics; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012550:Schistosoma mansoni / Q000201:enzymology*; D013050:Spectrometry, Fluorescence; D013237:Stereoisomerism; D013552:Swine; D000099240:Asparaginyl Endopeptidase
D001372:Aza Compounds; D003374:Coumarins; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors; D004852:Epoxy Compounds; D009842:Oligopeptides; D011994:Recombinant Proteins; D000099240:Asparaginyl Endopeptidase; C122092:benzyloxycarbonylalanyl-alanyl-asparaginyl-4-methyl-7-coumarylamide