Nature Communications (Oct 2016)
Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors
- Andrea M. Zuhl,
- Charles E. Nolan,
- Michael A. Brodney,
- Sherry Niessen,
- Kevin Atchison,
- Christopher Houle,
- David A. Karanian,
- Claude Ambroise,
- Jeffrey W. Brulet,
- Elizabeth M. Beck,
- Shawn D. Doran,
- Brian T. O’Neill,
- Christopher W. am Ende,
- Cheng Chang,
- Kieran F. Geoghegan,
- Graham M. West,
- Joshua C. Judkins,
- Xinjun Hou,
- David R. Riddell,
- Douglas S. Johnson
Affiliations
- Andrea M. Zuhl
- Pfizer Worldwide Research and Development
- Charles E. Nolan
- Pfizer Worldwide Research and Development
- Michael A. Brodney
- Pfizer Worldwide Research and Development
- Sherry Niessen
- Worldwide Medicinal Chemistry
- Kevin Atchison
- Pfizer Worldwide Research and Development
- Christopher Houle
- Pfizer Worldwide Research and Development
- David A. Karanian
- Pfizer Worldwide Research and Development
- Claude Ambroise
- Pfizer Worldwide Research and Development
- Jeffrey W. Brulet
- Pfizer Worldwide Research and Development
- Elizabeth M. Beck
- Pfizer Worldwide Research and Development
- Shawn D. Doran
- Pfizer Worldwide Research and Development
- Brian T. O’Neill
- Worldwide Medicinal Chemistry
- Christopher W. am Ende
- Worldwide Medicinal Chemistry
- Cheng Chang
- Pfizer Worldwide Research and Development
- Kieran F. Geoghegan
- Worldwide Medicinal Chemistry
- Graham M. West
- Worldwide Medicinal Chemistry
- Joshua C. Judkins
- Pfizer Worldwide Research and Development
- Xinjun Hou
- Pfizer Worldwide Research and Development
- David R. Riddell
- Pfizer Worldwide Research and Development
- Douglas S. Johnson
- Pfizer Worldwide Research and Development
- DOI
- https://doi.org/10.1038/ncomms13042
- Journal volume & issue
-
Vol. 7,
no. 1
pp. 1 – 14
Abstract
Several β-secretase (BACE) inhibitors exhibit unexplained ocular toxicity in preclinical studies. Here the authors generate a clickable photoaffinity probe to interrogate off-targets in cells and animals, and identify inhibition of cathepsin D as a driver of ocular toxicity.
