Design, synthesis, and evaluation of aza-peptide Michael acceptors as selective and potent inhibitors of caspases-2, -3, -6, -7, -8, -9, and -10.
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.
Ekici
Ozlem Dogan
OD
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332-0400, USA.
Li
Zhao Zhao
ZZ
Campbell
Amy J
AJ
James
Karen Ellis
KE
Asgian
Juliana L
JL
Mikolajczyk
Jowita
J
Salvesen
Guy S
GS
Ganesan
Rajkumar
R
Jelakovic
Stjepan
S
Grütter
Markus G
MG
Powers
James C
JC
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
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