Mechanistic and Structural Understanding of Uncompetitive Inhibitors of Caspase-6

作者：Heise Christopher E^*; Murray Jeremy; Augustyn Katherine E; Bravo Brandon; Chugha Preeti; Cohen Frederick; Giannetti Anthony M; Gibbons Paul; Hannoush Rami N; Hearn Brian R; Jaishankar Priyadarshini; Ly Cuong Q; Shah Kinjalkumar; Stanger Karen; Steffek Micah; Tang Yinyan; Zhao Xianrui; Lewcock Joseph W; Renslo Adam R; Flygare John; Arkin Michelle R

来源：PLos One, 2012, 7(12): e50864.

DOI：10.1371/journal.pone.0050864

Inhibition of caspase-6 is a potential therapeutic strategy for some neurodegenerative diseases, but it has been difficult to develop selective inhibitors against caspases. We report the discovery and characterization of a potent inhibitor of caspase-6 that acts by an uncompetitive binding mode that is an unprecedented mechanism of inhibition against this target class. Biochemical assays demonstrate that, while exquisitely selective for caspase-6 over caspase-3 and -7, the compound's inhibitory activity is also dependent on the amino acid sequence and P1' character of the peptide substrate. The crystal structure of the ternary complex of caspase-6, substrate-mimetic and an 11 nM inhibitor reveals the molecular basis of inhibition. The general strategy to develop uncompetitive inhibitors together with the unique mechanism described herein provides a rationale for engineering caspase selectivity.

• 出版日期2012-12-5