Tadalafil Rescues the p.M325T Mutant of Best1 Chloride Channel

Kathleen Elverson, Jim Warwicker, Sally Freeman, Forbes Manson

Research output: Contribution to journalArticlepeer-review

Abstract

Bestrophin 1 (Best1) is a chloride channel that localises to the plasma membrane of retinal pigment epithelium (RPE) cells. Mutations in the BEST1 gene are associated with a group of untreatable inherited retinal dystrophies (IRDs) called bestrophinopathies, caused by protein instability and loss-of-function of the Best1 protein. 4PBA and 2-NOAA have been shown to rescue the function, expression, and localisation of Best1 mutants; however, it is of interest to find more potent analogues as the concentration of the drugs required is too high (2.5 mM) to be given therapeutically. A virtual docking model of the COPII Sec24a site, where 4PBA has been shown to bind, was generated and a library of 1416 FDA-approved compounds was screened at the site. The top binding compounds were tested in vitro in whole-cell patch-clamp experiments of HEK293T cells expressing mutant Best1. The application of 25 μM tadalafil resulted in full rescue of Cl− conductance, comparable to wild type Best1 levels, for p.M325T mutant Best1 but not for p.R141H or p.L234V mutants.
Original languageEnglish
Article number3317
JournalMolecules
Volume28
Issue number8
Early online date8 Apr 2023
DOIs
Publication statusE-pub ahead of print - 8 Apr 2023

Keywords

  • bestrophin
  • IRDs
  • virtual docking
  • FDA-approved
  • COPII
  • 4PBA
  • tadalafil
  • whole-cell patch-clamp

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