title: An optimized InCell Western screening technique identifies hexachlorophene as a novel potent TDP43 targeting drug.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA.
authors.forename: Malathi
authors.initials: M
authors.lastname: Narayan
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Peralta
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Gibson
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Zitnyar
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA. Electronic address: UJinwal@health.usf.edu.
authors.forename: Umesh K
authors.initials: UK
authors.lastname: Jinwal
mesh_terms: D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D057809:HEK293 Cells; D006367:HeLa Cells; D006582:Hexachlorophene / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D057177:TDP-43 Proteinopathies / Q000188:drug therapy
chemical_list: D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human; D006582:Hexachlorophene
keywords: Alzheimer's disease; Amyotrophic lateral sclerosis; Fronto-temporal lobe dementia; Hexachlorophene; InCell Western; TDP43 proteinopathies