An optimized InCell Western screening technique identifies hexachlorophene as a novel potent TDP43 targeting drug
| Autor: | Malathi Narayan, Ashley Zitnyar, Chelsea Gibson, Umesh K. Jinwal, Diego A. Peralta |
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| Rok vydání: | 2014 |
| Předmět: |
Drug
media_common.quotation_subject Hexachlorophene Mutant Bioengineering Endogeny Applied Microbiology and Biotechnology Cell Line HeLa Mice mental disorders Drug Discovery medicine Animals Humans Molecular Targeted Therapy Amyotrophic lateral sclerosis media_common biology HEK 293 cells General Medicine biology.organism_classification medicine.disease Molecular biology DNA-Binding Proteins Cytosol HEK293 Cells Biochemistry TDP-43 Proteinopathies Biotechnology medicine.drug HeLa Cells |
| Zdroj: | Journal of biotechnology. 207 |
| ISSN: | 1873-4863 |
| Popis: | TAR DNA binding protein (TDP43) is a DNA- and RNA-binding protein that is implicated in several neurodegenerative disorders termed as "TDP43 proteinopathies" including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and fronto-temporal lobe dementia (FTLD). We have developed an InCell Western (ICW) technique for screening TDP targeting drugs in 96 well plates. We tested 281 compounds and identified a novel compound hexachlorophene (referred to as B10) that showed potent reduction in TDP43 levels. The effect of B10 on TDP protein level was validated in two different cellular models: endogenous TDP43 expressing N9 microglial cells and TDP43-over-expressing HEK293 and HeLa cells. We also analyzed effect of B10 on various pathological forms of TDP such as the C25 cleaved fragment that localizes to the cytosol, insoluble high molecular weight species, and ALS-linked mutants. Our data suggest that B10 effectively reduces all forms of TDP. Overall, our data suggest that B10 could serve as a potential drug molecule for the treatment of AD, ALS and other TDP43 proteinopathies. |
| Databáze: | OpenAIRE |
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