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Drug Library Screening for the Identification of Ionophores That Correct the Mistrafficking Disorder Associated with Oxalosis Kidney Disease.
- Source :
-
SLAS discovery : advancing life sciences R & D [SLAS Discov] 2017 Aug; Vol. 22 (7), pp. 887-896. Date of Electronic Publication: 2017 Jan 31. - Publication Year :
- 2017
-
Abstract
- Primary hyperoxaluria is the underlying cause of oxalosis and is a life-threatening autosomal recessive disease, for which treatment may require dialysis or dual liver-kidney transplantation. The most common primary hyperoxaluria type 1 (PH1) is caused by genetic mutations of a liver-specific enzyme alanine:glyoxylate aminotransferase (AGT), which results in the misrouting of AGT from the peroxisomes to the mitochondria. Pharmacoperones are small molecules with the ability to modify misfolded proteins and route them correctly within the cells, which may present an effective strategy to treat AGT misrouting in PH1 disorders. We miniaturized a cell-based high-content assay into 1536-well plate format and screened ~4200 pharmacologically relevant compounds including Food and Drug Administration, European Union, and Japanese-approved drugs. This assay employs CHO cells stably expressing AGT-170, a mutant that predominantly resides in the mitochondria, where we monitor for its relocation to the peroxisomes through automated image acquisition and analysis. The miniaturized 1536-well assay yielded a Z' averaging 0.70 ± 0.07. Three drugs were identified as potential pharmacoperones from this pilot screen, demonstrating the applicability of this assay for large-scale high-throughput screening.
- Subjects :
- Animals
CHO Cells
Cricetulus
Drug Evaluation, Preclinical methods
Hyperoxaluria genetics
Hyperoxaluria metabolism
Hyperoxaluria, Primary drug therapy
Hyperoxaluria, Primary genetics
Hyperoxaluria, Primary metabolism
Kidney Diseases genetics
Kidney Diseases metabolism
Kidney Transplantation methods
Liver drug effects
Liver metabolism
Mitochondria drug effects
Mitochondria genetics
Mitochondria metabolism
Mutation genetics
Peroxisomes drug effects
Peroxisomes genetics
Peroxisomes metabolism
Renal Dialysis methods
Transaminases genetics
Transaminases metabolism
Hyperoxaluria drug therapy
Ionophores pharmacology
Kidney Diseases drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 2472-5560
- Volume :
- 22
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- SLAS discovery : advancing life sciences R & D
- Publication Type :
- Academic Journal
- Accession number :
- 28346094
- Full Text :
- https://doi.org/10.1177/2472555217689992