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Rescue of Mutant CFTR Trafficking Defect by the Investigational Compound MCG1516A.
Lopes-Pacheco, Miquéias; Bacalhau, Mafalda; Ramalho, Sofia S; Silva, Iris A L; Ferreira, Filipa C; Carlile, Graeme W; Thomas, David Y; Farinha, Carlos M; Hanrahan, John W; Amaral, Margarida D.
Afiliación
  • Lopes-Pacheco M; Faculty of Sciences, Biosystems & Integrative Sciences Institute (BioISI), University of Lisbon, 1749-016 Lisbon, Portugal.
  • Bacalhau M; Faculty of Sciences, Biosystems & Integrative Sciences Institute (BioISI), University of Lisbon, 1749-016 Lisbon, Portugal.
  • Ramalho SS; Faculty of Sciences, Biosystems & Integrative Sciences Institute (BioISI), University of Lisbon, 1749-016 Lisbon, Portugal.
  • Silva IAL; Faculty of Sciences, Biosystems & Integrative Sciences Institute (BioISI), University of Lisbon, 1749-016 Lisbon, Portugal.
  • Ferreira FC; Faculty of Sciences, Biosystems & Integrative Sciences Institute (BioISI), University of Lisbon, 1749-016 Lisbon, Portugal.
  • Carlile GW; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
  • Thomas DY; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
  • Farinha CM; Faculty of Sciences, Biosystems & Integrative Sciences Institute (BioISI), University of Lisbon, 1749-016 Lisbon, Portugal.
  • Hanrahan JW; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
  • Amaral MD; Faculty of Sciences, Biosystems & Integrative Sciences Institute (BioISI), University of Lisbon, 1749-016 Lisbon, Portugal.
Cells ; 11(1)2022 01 01.
Article en En | MEDLINE | ID: mdl-35011698
Although some therapeutic progress has been achieved in developing small molecules that correct F508del-CFTR defects, the mechanism of action (MoA) of these compounds remain poorly elucidated. Here, we investigated the effects and MoA of MCG1516A, a newly developed F508del-CFTR corrector. MCG1516A effects on wild-type (WT) and F508del-CFTR were assessed by immunofluorescence microscopy, and biochemical and functional assays both in cell lines and in intestinal organoids. To shed light on the MoA of MCG1516A, we evaluated its additivity to the FDA-approved corrector VX-661, low temperature, genetic revertants of F508del-CFTR (G550E, R1070W, and 4RK), and the traffic-null variant DD/AA. Finally, we explored the ability of MCG1516A to rescue trafficking and function of other CF-causing mutations. We found that MCG1516A rescues F508del-CFTR with additive effects to VX-661. A similar behavior was observed for WT-CFTR. Under low temperature incubation, F508del-CFTR demonstrated an additivity in processing and function with VX-661, but not with MCG1516A. In contrast, both compounds promoted additional effects to low temperature to WT-CFTR. MCG1516A demonstrated additivity to genetic revertant R1070W, while VX-661 was additive to G550E and 4RK. Nevertheless, none of these compounds rescued DD/AA trafficking. Both MCG1516A and VX-661 rescued CFTR processing of L206W- and R334W-CFTR with greater effects when these compounds were combined. In summary, the absence of additivity of MCG1516A to genetic revertant G550E suggests a putative binding site for this compound on NBD1:NBD2 interface. Therefore, a combination of MCG1516A with compounds able to rescue DD/AA traffic, or mimicking the actions of revertant R1070W (e.g., VX-661), could enhance correction of F508del-CFTR defects.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulador de Conductancia de Transmembrana de Fibrosis Quística / Fibrosis Quística / Descubrimiento de Drogas Límite: Humans Idioma: En Revista: Cells Año: 2022 Tipo del documento: Article País de afiliación: Portugal Pais de publicación: Suiza
Texto completo
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Imprimir
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulador de Conductancia de Transmembrana de Fibrosis Quística / Fibrosis Quística / Descubrimiento de Drogas Límite: Humans Idioma: En Revista: Cells Año: 2022 Tipo del documento: Article País de afiliación: Portugal Pais de publicación: Suiza