Design, synthesis, and evaluation of aza-peptide epoxides as selective and potent inhibitors of caspases-1, -3, -6, and -8.
Aza-peptide epoxides, a novel class of irreversible protease inhibitors, are specific for the clan CD cysteine proteases. Aza-peptide epoxides with an aza-Asp residue at P1 are excellent irreversible inhibitors of caspases-1, -3, -6, and -8 with second-order inhibition rates up to 1 910 000 M(-1) s(-1). In general, the order of reactivity of aza-peptide epoxides is S,S > R,R > trans > cis. Interestingly, some of the R,R epoxides while being less potent are actually more selective than the S,S epoxides. Our aza-peptide epoxides designed for caspases are stable, potent, and specific inhibitors, as they show little to no inhibition of other proteases such as the aspartyl proteases porcine pepsin, human cathepsin D, plasmepsin 2 from P. falciparum, HIV-1 protease, and the secreted aspartic proteinase 2 (SAP-2) from Candida albicans; the serine proteases granzyme B and alpha-chymotrypsin; and the cysteine proteases cathepsin B and papain (clan CA), and legumain (clan CD).
James
Karen Ellis
KE
School of Chemistry and Biochemistry and the Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332-0400, USA.
Asgian
Juliana L
JL
Li
Zhao Zhao
ZZ
Ekici
Ozlem Doğan
OD
Rubin
John R
JR
Mikolajczyk
Jowita
J
Salvesen
Guy S
GS
Powers
James C
JC
D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D020170:Caspase 1 / Q000737:chemistry; D053148:Caspase 3; D053178:Caspase 6; D053181:Caspase 8; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D004355:Drug Stability; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001372:Aza Compounds; D061945:Caspase Inhibitors; D004852:Epoxy Compounds; D009842:Oligopeptides; C505407:CASP3 protein, human; C505514:CASP6 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053178:Caspase 6; D053181:Caspase 8; D020169:Caspases; D020170:Caspase 1