1. Academic Validation
  2. A small molecule screen identifies selective inhibitors of urea transporter UT-A

A small molecule screen identifies selective inhibitors of urea transporter UT-A

  • Chem Biol. 2013 Oct 24;20(10):1235-44. doi: 10.1016/j.chembiol.2013.08.005.
Cristina Esteva-Font 1 Puay-Wah Phuan Marc O Anderson A S Verkman
Affiliations

Affiliation

  • 1 Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, CA 94143-0521, USA.
Abstract

Urea Transporter (UT) proteins, including UT-A in kidney tubule epithelia and UT-B in vasa recta microvessels, facilitate urinary concentrating function. A screen for UT-A inhibitors was developed in MDCK cells expressing UT-A1, water channel aquaporin-1, and YFP-H148Q/V163S. An inwardly directed urea gradient produces cell shrinking followed by UT-A1-dependent swelling, which was monitored by YFP-H148Q/V163S fluorescence. Screening of ~90,000 synthetic small molecules yielded four classes of UT-A1 inhibitors with low micromolar half-maximal inhibitory concentration that fully and reversibly inhibited urea transport by a noncompetitive mechanism. Structure-activity analysis of >400 analogs revealed UT-A1-selective and UT-A1/UT-B nonselective inhibitors. Docking computations based on homology models of UT-A1 suggested inhibitor binding sites. UT-A inhibitors may be useful as diuretics ("urearetics") with a mechanism of action that may be effective in fluid-retaining conditions in which conventional salt transport-blocking diuretics have limited efficacy.

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