Peptide-based, irreversible inhibitors of γ-secretase activity

Siân C. Piper, Zareen Amtul, Laura Galiñanes-Garcia, Victor G. Howard, Chewki Ziani-Cherif, Chris McLendon, Marjorie J. Rochette, Abdul Fauq, Todd E. Golde, M. Paul Murphy

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


The characterization of the enzymes responsible for amyloid β-peptide (Aβ) production is considered to be a primary goal towards the development of future therapeutics for the treatment of Alzheimer's disease. Inhibitors of γ-secretase activity were critical in demonstrating that the presenilins (PSs) likely comprised at least part of the active site of the γ-secretase enzyme complex, with two highly conserved membrane aspartates presumably acting as catalytic residues. However, whether or not these aspartates are actually the catalytic residues of the enzyme complex or are merely essential for normal PS function and/or maturation is still unknown. In this paper, we report the development of reactive inhibitors of γ-secretase activity that are functionally irreversible. Since such inhibitors have been shown to bind catalytic residues in other aspartyl proteases (e.g., HIV protease), they might be used to determine if the transmembrane aspartates of PSs are involved directly in substrate cleavage.

Original languageEnglish
Pages (from-to)529-533
Number of pages5
JournalBiochemical and Biophysical Research Communications
Issue number3
StatePublished - Jun 6 2003

Bibliographical note

Funding Information:
The authors would like to thank B. Greenberg (Ab207) and Takeda Industries (BA27 and BC05) for providing antibodies, and R. Kopan for providing the NδE construct. This work was supported by an Ellison Medical Foundation New Scholars award and NIH Grant NS39072 (T.E.G.), Robert and Clarice Smith Neurodegenerative Disease and Stroke fellowships (to M.P.M.), and by the Mayo Foundation.


  • Alzheimer's disease
  • Amyloid-β peptide
  • Amyloid-β protein precursor
  • Notch
  • Presenilin
  • γ-Secretase

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology


Dive into the research topics of 'Peptide-based, irreversible inhibitors of γ-secretase activity'. Together they form a unique fingerprint.

Cite this