Linear non-competitive inhibition of solubilized human gamma-secretase by pepstatin A methylester, L685458, sulfonamides, and benzodiazepines.
Cerebral deposition of amyloid beta-protein (A beta) is believed to play a key role in the pathogenesis of Alzheimer's disease. Because A beta is produced from the processing of amyloid beta-protein precursor (APP) by beta- and gamma-secretases, these enzymes are considered important therapeutic targets for identification of drugs to treat Alzheimer's disease. Unlike beta-secretase, which is a monomeric aspartyl protease, gamma-secretase activity resides as part of a membrane-bound, high molecular weight, macromolecular complex. Pepstatin and L685458 are among several structural classes of gamma-secretase inhibitors identified so far. These compounds possess a hydroxyethylene dipeptide isostere of aspartyl protease transition state analogs, suggesting gamma-secretase may be an aspartyl protease. However, the mechanism of inhibition of gamma-secretase by pepstatin and L685458 has not been elucidated. In this study, we report that pepstatin A methylester and L685458 unexpectedly displayed linear non-competitive inhibition of gamma-secretase. Sulfonamides and benzodiazepines, which do not resemble transition state analogs of aspartyl proteases, also displayed potent, non-competitive inhibition of gamma-secretase. Models to rationalize how transition state analogs inhibit their targets by non-competitive inhibition are discussed.
Tian
Gaochao
G
Department of Lead Discovery, AstraZeneca Pharmaceuticals, Wilmington, Delaware 19850, USA. gaochao.tian@astrazeneca.com
Sobotka-Briner
Cynthia D
CD
Zysk
John
J
Liu
Xiaodong
X
Birr
Cynthia
C
Sylvester
Mark A
MA
Edwards
Philip D
PD
Scott
Clay D
CD
Greenberg
Barry D
BD
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D001569:Benzodiazepines / Q000494:pharmacology*; D001665:Binding Sites; D002219:Carbamates / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology*; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D010436:Pepstatins / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000494:pharmacology*
D002219:Carbamates; D004151:Dipeptides; C410009:L 685458; D010436:Pepstatins; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D013449:Sulfonamides; D001569:Benzodiazepines; C014247:pepstatyl-arginine methyl ester; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human