BIBLIOS

Document type
Journal articles

Document subtype
Full paper

Title
Rescue of Mutant CFTR Trafficking Defect by the Investigational Compound MCG1516A

Participants in the publication
Miquéias Lopes-Pacheco (Author)
Dep. Química e Bioquímica
BioISI
Mafalda Bacalhau (Author)
Sofia S. Ramalho (Author)
Iris A. L. Silva (Author)
Filipa C. Ferreira (Author)
Graeme W. Carlile (Author)
David Y. Thomas (Author)
Carlos M. Farinha (Author)
Dep. Química e Bioquímica
BioISI
John W. Hanrahan (Author)
Margarida D. Amaral (Author)
Dep. Química e Bioquímica
BioISI

Summary
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.


Where published
Cells

Publication Identifiers
ISSN - 2073-4409

Publisher
MDPI AG



Document Identifiers
DOI - https://doi.org/10.3390/cells11010136
URL - http://dx.doi.org/10.3390/cells11010136

Rankings
SCIMAGO Q1 (2020) - 1.22 - Medicine (miscellaneous)
SCIMAGO Q1 (2017) - 2.742 - Biochemistry, Genetics and Molecular Biology (miscellaneous)

Download