Brain-Permeable Small-Molecule Inhibitors of Hsp90 Prevent α-Synuclein Oligomer Formation and Rescue α-Synuclein-Induced Toxicity
| Autor: | Carol D. Hicks, Sarah R. Mabbett, James Marvin Veal, Karin M Danzer, Bradley T. Hyman, Melanie Silinski, Lisa R. Kranich, Preeti Putcha, Anisa Scott, Pamela J. McLean, Paul M. Steed |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Cellular and Molecular
Cell Membrane Permeability Indoles Administration Oral Biological Availability Transfection Hsp90 inhibitor Rats Sprague-Dawley chemistry.chemical_compound Structure-Activity Relationship Protein-fragment complementation assay Heat shock protein medicine Animals Humans ortho-Aminobenzoates HSP90 Heat-Shock Proteins Cytotoxicity Pharmacology Alpha-synuclein biology Dementia with Lewy bodies Brain Geldanamycin medicine.disease Hsp90 Rats Biochemistry chemistry Benzamides biology.protein alpha-Synuclein Molecular Medicine Female |
| Popis: | Aggregation of alpha-synuclein (alphasyn) is a hallmark of sporadic and familial Parkinson's disease (PD) and dementia with Lewy bodies. Lewy bodies contain alphasyn and several heat shock proteins (Hsp), a family of molecular chaperones up-regulated by the cell under stress. We have previously shown that direct expression of Hsp70 and pharmacological up-regulation of Hsp70 by geldanamycin, an Hsp90 inhibitor, are protective against alphasyn-induced toxicity and prevent aggregation in culture. Here, we use a novel protein complementation assay to screen a series of small-molecule Hsp90 inhibitors for their ability to prevent alphasyn oligomerization and rescue toxicity. By use of this assay, we found that several compounds prevented alphasyn oligomerization as measured by decreased luciferase activity, led to a reduction in high-molecular-mass oligomeric alphasyn, and protected against alphasyn cytotoxicity. A lead compound, SNX-0723 (2-fluoro-6-[(3S)-tetrahydrofuran-3-ylamino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide) was determined to have an EC(50) for inhibition of alphasyn oligomerization of approximately 48 nM and was able to rescue alphasyn-induced toxicity. In vivo assessment of SNX-0723 showed significant brain concentrations along with induction of brain Hsp70. With a low EC(50), brain permeability, and oral availability, these novel inhibitors represent an exciting new therapeutic strategy for PD. |
| Databáze: | OpenAIRE |
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