Linear non-competitive inhibition of solubilized human γ-secretase by pepstatin A methylester, L685458, sulfonamides, and benzodiazepines

Gaochao Tian, Cynthia D. Sobotka-Briner, John Zysk, Xiaodong Liu, Cynthia Birr, Mark A. Sylvester, Philip D. Edwards, Clay D. Scott, Barry D. Greenberg

Research output: Contribution to journalArticle

Abstract

Cerebral deposition of amyloid β-protein (Aβ) is believed to play a key role in the pathogenesis of Alzheimer's disease. Because Aβ is produced from the processing of amyloid β-protein precursor (APP) by β- and γ-secretases, these enzymes are considered important therapeutic targets for identification of drugs to treat Alzheimer's disease. Unlike β-secretase, which is a monomeric aspartyl protease, γ-secretase activity resides as part of a membrane-bound, high molecular weight, macromolecular complex. Pepstatin and L685458 are among several structural classes of γ-secretase inhibitors identified so far. These compounds possess a hydroxyethylene dipeptide isostere of aspartyl protease transition state analogs, suggesting γ-secretase may be an aspartyl protease. However, the mechanism of inhibition of γ-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 γ-secretase. Sulfonamides and benzodiazepines, which do not resemble transition state analogs of aspartyl proteases, also displayed potent, non-competitive inhibition of γ-secretase. Models to rationalize how transition state analogs inhibit their targets by non-competitive inhibition are discussed.

Original languageEnglish (US)
Pages (from-to)31499-31505
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number35
DOIs
StatePublished - Aug 30 2002
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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