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Article

Rescue of Mutant CFTR Trafficking Defect by the Investigational Compound MCG1516A

by
Miquéias Lopes-Pacheco
1,*,
Mafalda Bacalhau
1,
Sofia S. Ramalho
1,
Iris A. L. Silva
1,
Filipa C. Ferreira
1,
Graeme W. Carlile
2,
David Y. Thomas
2,
Carlos M. Farinha
1,
John W. Hanrahan
3 and
Margarida D. Amaral
1
1
Faculty of Sciences, Biosystems & Integrative Sciences Institute (BioISI), University of Lisbon, 1749-016 Lisbon, Portugal
2
Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
3
Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada
*
Author to whom correspondence should be addressed.
Cells 2022, 11(1), 136; https://doi.org/10.3390/cells11010136
Submission received: 20 November 2021 / Revised: 20 December 2021 / Accepted: 22 December 2021 / Published: 1 January 2022
(This article belongs to the Collection Cystic Fibrosis: Cells, Physiopathology and Emerging Therapies)
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Abstract

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.
Keywords: cystic fibrosis; drug discovery; F508del-CFTR; genetic revertants; intestinal organoids; low temperature; protein trafficking; rare mutations cystic fibrosis; drug discovery; F508del-CFTR; genetic revertants; intestinal organoids; low temperature; protein trafficking; rare mutations
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MDPI and ACS Style

Lopes-Pacheco, M.; Bacalhau, M.; Ramalho, S.S.; Silva, I.A.L.; Ferreira, F.C.; Carlile, G.W.; Thomas, D.Y.; Farinha, C.M.; Hanrahan, J.W.; Amaral, M.D. Rescue of Mutant CFTR Trafficking Defect by the Investigational Compound MCG1516A. Cells 2022, 11, 136. https://doi.org/10.3390/cells11010136

AMA Style

Lopes-Pacheco M, Bacalhau M, Ramalho SS, Silva IAL, Ferreira FC, Carlile GW, Thomas DY, Farinha CM, Hanrahan JW, Amaral MD. Rescue of Mutant CFTR Trafficking Defect by the Investigational Compound MCG1516A. Cells. 2022; 11(1):136. https://doi.org/10.3390/cells11010136

Chicago/Turabian Style

Lopes-Pacheco, Miquéias, Mafalda Bacalhau, Sofia S. Ramalho, Iris A. L. Silva, Filipa C. Ferreira, Graeme W. Carlile, David Y. Thomas, Carlos M. Farinha, John W. Hanrahan, and Margarida D. Amaral. 2022. "Rescue of Mutant CFTR Trafficking Defect by the Investigational Compound MCG1516A" Cells 11, no. 1: 136. https://doi.org/10.3390/cells11010136

APA Style

Lopes-Pacheco, M., Bacalhau, M., Ramalho, S. S., Silva, I. A. L., Ferreira, F. C., Carlile, G. W., Thomas, D. Y., Farinha, C. M., Hanrahan, J. W., & Amaral, M. D. (2022). Rescue of Mutant CFTR Trafficking Defect by the Investigational Compound MCG1516A. Cells, 11(1), 136. https://doi.org/10.3390/cells11010136

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