Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors
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.
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2016-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/ncomms13042 |
| _version_ | 1818978516032552960 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Andrea M. Zuhl |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T16:44:52Z |
| format | Article |
| id | doaj.art-5dfe4a29e6af43a49ee6c24207abc513 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-12-20T16:44:52Z |
| publishDate | 2016-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-5dfe4a29e6af43a49ee6c24207abc5132022-12-21T19:32:57ZengNature PortfolioNature Communications2041-17232016-10-017111410.1038/ncomms13042Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitorsAndrea M. Zuhl0Charles E. Nolan1Michael A. Brodney2Sherry Niessen3Kevin Atchison4Christopher Houle5David A. Karanian6Claude Ambroise7Jeffrey W. Brulet8Elizabeth M. Beck9Shawn D. Doran10Brian T. O’Neill11Christopher W. am Ende12Cheng Chang13Kieran F. Geoghegan14Graham M. West15Joshua C. Judkins16Xinjun Hou17David R. Riddell18Douglas S. Johnson19Pfizer Worldwide Research and DevelopmentPfizer Worldwide Research and DevelopmentPfizer Worldwide Research and DevelopmentWorldwide Medicinal ChemistryPfizer Worldwide Research and DevelopmentPfizer Worldwide Research and DevelopmentPfizer Worldwide Research and DevelopmentPfizer Worldwide Research and DevelopmentPfizer Worldwide Research and DevelopmentPfizer Worldwide Research and DevelopmentPfizer Worldwide Research and DevelopmentWorldwide Medicinal ChemistryWorldwide Medicinal ChemistryPfizer Worldwide Research and DevelopmentWorldwide Medicinal ChemistryWorldwide Medicinal ChemistryPfizer Worldwide Research and DevelopmentPfizer Worldwide Research and DevelopmentPfizer Worldwide Research and DevelopmentPfizer Worldwide Research and DevelopmentSeveral 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.https://doi.org/10.1038/ncomms13042 |
| spellingShingle | 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 Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors Nature Communications |
| title | Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors |
| title_full | Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors |
| title_fullStr | Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors |
| title_full_unstemmed | Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors |
| title_short | Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors |
| title_sort | chemoproteomic profiling reveals that cathepsin d off target activity drives ocular toxicity of β secretase inhibitors |
| url | https://doi.org/10.1038/ncomms13042 |
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