Rapid Identification of Novel Inhibitors of the Human Aquaporin-1 Water Channel
| Autor: | Zixia Feng, Tom Brittain, Mark R. Hellberg, Grant Carr, Jesse A. May, Macarena Irigoyen, Damon Colbert, Shouxi Xu, Alfred N. Van Hoek, Peter M. Brown, Rajkumar V. Patil, Alok K. Mitra, Kulandaiappan Varadaraj, M. B. Wax, Andrew Rusinko, Najam A. Sharif, S. Sindhu Kumari |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Aquaporin CHO Cells Pharmacology Biology Biochemistry Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cricetulus Cricetinae Drug Discovery medicine Animals Humans Water transport Aquaporin 1 Organic Chemistry Membrane transport Pulmonary edema medicine.disease Calcein 030104 developmental biology Aquaporin 4 chemistry Membrane protein Molecular Medicine 030217 neurology & neurosurgery |
| Zdroj: | Chemical biologydrug design. 87(5) |
| ISSN: | 1747-0285 |
| Popis: | Aquaporins (AQPs) are a family of membrane proteins that function as channels facilitating water transport in response to osmotic gradients. These play critical roles in several normal physiological and pathological states and are targets for drug discovery. Selective inhibition of the AQP1 water channel may provide a new approach for the treatment of several disorders including ocular hypertension/glaucoma, congestive heart failure, brain swelling associated with a stroke, corneal and macular edema, pulmonary edema, and otic disorders such as hearing loss and vertigo. We developed a high-throughput assay to screen a library of compounds as potential AQP1 modulators by monitoring the fluorescence dequenching of entrapped calcein in a confluent layer of AQP1-overexpressing CHO cells that were exposed to a hypotonic shock. Promising candidates were tested in a Xenopus oocyte-swelling assay, which confirmed the identification of two lead classes of compounds belonging to aromatic sulfonamides and dihydrobenzofurans with IC50 s in the low micromolar range. These selected compounds directly inhibited water transport in AQP1-enriched stripped erythrocyte ghosts and in proteoliposomes reconstituted with purified AQP1. Validation of these lead compounds, by the three independent assays, establishes a set of attractive AQP1 blockers for developing novel, small-molecule functional modulators of human AQP1. |
| Databáze: | OpenAIRE |
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