Piperidine acetic acid based γ-secretase modulators directly bind to presenilin-1 Journal Article
| Authors: | Crump, C. J.; Fish, B. A.; Castro, S. V.; Chau, D. M.; Gestsik, N.; Ahn, K.; Stiff, C.; Pozdnyakov, N.; Bales, K. R.; Johnson, D. S.; Li, Y. M. |
| Article Title: | Piperidine acetic acid based γ-secretase modulators directly bind to presenilin-1 |
| Abstract: | Aβ42 is believed to play a causative role in Alzheimer's disease (AD) pathogenesis. γ-Secretase modulators (GSMs) are actively being pursued as potential AD therapeutics because they selectively alter the cleavage site of the amyloid precursor protein (APP) to reduce the formation of Aβ42. However, the binding partner of acid based GSMs was unresolved until now. We have developed clickable photoaffinity probes based on piperidine acetic acid GSM-1 and identified PS1 as the target within the γ-secretase complex. Furthermore, we provide evidence that allosteric interaction of GSMs with PS1 results in a conformational change in the active site of the γ-secretase complex leading to the observed modulation of γ-secretase activity. © 2011 American Chemical Society. |
| Keywords: | human cell; drug structure; in vitro study; hela cell; drug synthesis; ic 50; drug protein binding; presenilin; gamma secretase; presenilin 1; photoaffinity labeling; click chemistry; alzheimer's disease; gsm-1; ; ritalinic acid |
| Journal Title: | ACS Chemical Neuroscience |
| Volume: | 2 |
| Issue: | 12 |
| ISSN: | 1948-7193 |
| Publisher: | American Chemical Society |
| Date Published: | 2011-12-21 |
| Start Page: | 705 |
| End Page: | 710 |
| Language: | English |
| DOI: | 10.1021/cn200098p |
| PROVIDER: | scopus |
| PMCID: | PMC3249837 |
| PUBMED: | 22229075 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 1 February 2012" - "Source: Scopus" |
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