Using peptidic inhibitors to systematically probe the S1' site of caspase-3 and caspase-7.
Fifteen ketone-containing peptides were designed, synthesized, and used to probe the effect of substitution at the P1' position on caspase-3 and -7 inhibition. Even with the large bias of Ac-Asp-Glu-Val-Asp at the P4-P1 positions, certain peptides with cyclic functionality in the P1' position show a dramatically reduced ability to inhibit these caspases. Additionally, trends toward isozyme selectivity were also uncovered for particular P1' substituents. The data indicate that substitution in the P1' position can drastically affect both caspase inhibition and selectivity. [structure: see text]
Goode
David R
DR
Roger Adams Laboratory, University of Illinois, Urbana, IL 61801, USA.
Sharma
Anil K
AK
Hergenrother
Paul J
PJ
D000595:Amino Acid Sequence; D053148:Caspase 3; D053179:Caspase 7; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D009842:Oligopeptides; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases