Rapid Identification of Novel Inhibitors of the Human Aquaporin-1 Water Channel

Rajkumar V. Patil, Shouxi Xu, Alfred N. van Hoek, Andrew Rusinko, Zixia Feng, Jesse May, Mark Hellberg, Najam A. Sharif, Martin B. Wax, Macarena Irigoyen, Grant Carr, Tom Brittain, Peter Brown, Damon Colbert, Sindhu Kumari, Kulandaiappan Varadaraj, Alok K. Mitra

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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 IC50s 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.

Original languageEnglish (US)
Pages (from-to)794-805
Number of pages12
JournalChemical Biology and Drug Design
Issue number5
StatePublished - May 1 2016


  • aquaporin
  • drug discovery
  • membrane transport
  • protein expression
  • water channel

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


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