Molecular Mechanism of Action of Trimethylangelicin Derivatives as CFTR Modulators

Frontiers in Pharmacology
Onofrio LaselvaMaria Cristina Dechecchi

Abstract

The psoralen-related compound, 4,6,4'-trimethylangelicin (TMA) potentiates the cAMP/PKA-dependent activation of WT-CFTR and rescues F508del-CFTR-dependent chloride secretion in both primary and secondary airway cells homozygous for the F508del mutation. We recently demonstrated that TMA, like lumacaftor (VX-809), stabilizes the first membrane-spanning domain (MSD1) and enhances the interface between NBD1 and ICL4 (MSD2). TMA also demonstrated anti-inflammatory properties, via reduction of IL-8 expression, thus making TMA a promising agent for treatment of cystic fibrosis. Unfortunately, TMA was also found to display potential phototoxicity and mutagenicity, despite the fact that photo-reactivity is absent when the compound is not directly irradiated with UVA light. Due to concerns about these toxic effects, new TMA analogs, characterized by identical or better activity profiles and minimized or reduced side effects, were synthesized by modifying specific structural features on the TMA scaffold, thus generating compounds with no mutagenicity and phototoxicity. Among these compounds, we found TMA analogs which maintained the potentiation activity of CFTR in FRT-YFP-G551D cells. Nanomolar concentrations of these analogs significan...Continue Reading

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Citations

Aug 28, 2020·Frontiers in Immunology·Giulio CabriniRoberto Gambari
Aug 4, 2020·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Onofrio LaselvaChristine E Bear
May 1, 2021·Journal of Personalized Medicine·Onofrio LaselvaChristine E Bear
Jun 4, 2020·Molecular Therapy. Methods & Clinical Development·Steven ErwoodEvgueni A Ivakine
Nov 7, 2021·BMC Medical Genomics·Consuelo Cantú-ReynaWillebaldo García-Muñoz

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Methods Mentioned

BETA
transfections
Fluorescence
electrophoresis
fluorescence imaging

Software Mentioned

ImageJ
Prism
KALYDECO
GraphPad

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