title: Design, synthesis, and evaluation of aza-peptide Michael acceptors as selective and potent inhibitors of caspases-2, -3, -6, -7, -8, -9, and -10.
abstract: Aza-peptide Michael acceptors are a novel class of inhibitors that are potent and specific for caspases-2, -3, -6, -7, -8, -9, and -10. The second-order rate constants are in the order of 10(6) M(-1) s(-1). The aza-peptide Michael acceptor inhibitor 18t (Cbz-Asp-Glu-Val-AAsp-trans-CH=CH-CON(CH(2)-1-Naphth)(2) is the most potent compound and it inhibits caspase-3 with a k(2) value of 5620000 M(-1) s(-1). The inhibitor 18t is 13700, 190, 6.4, 594, 37500, and 173-fold more selective for caspase-3 over caspases-2, -6, -7, -8, -9, and -10, respectively. Aza-peptide Michael acceptors designed with caspase specific sequences are selective and do not show any cross reactivity with clan CA cysteine proteases such as papain, cathepsin B, and calpains. High-resolution crystal structures of caspase-3 and caspase-8 in complex with aza-peptide Michael acceptor inhibitors demonstrate the nucleophilic attack on C2 and provide insight into the selectivity and potency of the inhibitors with respect to the P1' moiety.
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332-0400, USA.
authors.forename: Ozlem Dogan
authors.initials: OD
authors.lastname: Ekici
authors.forename: Zhao Zhao
authors.initials: ZZ
authors.lastname: Li
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Campbell
authors.forename: Karen Ellis
authors.initials: KE
authors.lastname: James
authors.forename: Juliana L
authors.initials: JL
authors.lastname: Asgian
authors.forename: Jowita
authors.initials: J
authors.lastname: Mikolajczyk
authors.forename: Guy S
authors.initials: GS
authors.lastname: Salvesen
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Ganesan
authors.forename: Stjepan
authors.initials: S
authors.lastname: Jelakovic
authors.forename: Markus G
authors.initials: MG
authors.lastname: Grütter
authors.forename: James C
authors.initials: JC
authors.lastname: Powers
mesh_terms: D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D053455:Caspase 10; D053143:Caspase 2; D053148:Caspase 3; D053178:Caspase 6; D053179:Caspase 7; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry; D018360:Crystallography, X-Ray; D007700:Kinetics; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D001372:Aza Compounds; D061945:Caspase Inhibitors; C514171:N,N-bis(1-naphthyl)methyl benzyloxycarbonyl-aspartyl-glutamyl-valyl-azaaspartylpropenamide; D009842:Oligopeptides; D053455:Caspase 10; D053143:Caspase 2; D053148:Caspase 3; D053178:Caspase 6; D053179:Caspase 7; D053453:Caspase 9; D020169:Caspases