Document type
Journal articles
Document subtype
Full paper
Title
Characterization of the mechanism of action of RDR01752, a novel corrector of F508del-CFTR
Participants in the publication
Miquéias Lopes-Pacheco (Author)
BioISI - Biosystems & Integrative Sciences Institute
Dep. Química e Bioquímica
BioISI
Iris A.L. Silva (Author)
Mark J. Turner (Author)
Graeme W. Carlile (Author)
Elvira Sondo (Author)
David Y. Thomas (Author)
Nicoletta Pedemonte (Author)
John W. Hanrahan (Author)
Margarida D. Amaral (Author)
Dep. Química e Bioquímica
BioISI
Summary
Despite progress in developing pharmacotherapies to rescue F508del-CFTR, the most prevalent Cystic Fibrosis (CF)-causing mutation, individuals homozygous for this mutation still face several disease-related symptoms. Thus, more potent compound combinations are still needed. Here, we investigated the mechanism of action (MoA) of RDR01752, a novel F508del-CFTR trafficking corrector. F508del-CFTR correction by RDR01752 was assessed by biochemical, immunofluorescence microscopy and functional assays in cell lines and in intestinal organoids. To determine the MoA of RDR01752, we assessed its additive effects to those of genetic revertants of F508del-CFTR, the FDA-approved corrector drugs VX-809 and VX-661, and low temperature. Our data demonstrated that RDR01752 rescues F508del-CFTR processing and plasma membrane (PM) expression to similar levels of VX-809 in cell lines, although RDR01752 produced lower functional rescue. However, in functional assays using intestinal organoids (F508del/F508del), RDR01752, VX-809 and VX-661 had similar efficacy. RDR01752 demonstrated additivity to revertants 4RK and G550E, but not to R1070W, as previously shown for VX-809. RDR01752 was also additive to low temperature. Co-treatment of RDR01752 and VX-809 did not increase F508del-CFTR PM expression and function compared to each corrector alone. The lack of additivity of RDR01752 with the genetic revertant R1070W suggests that this compound has the same effect as the insertion of tryptophan at 1070, i.e., filling the pocket at the NBD1:ICL4 interface in F508del-CFTR, similarly to VX-809. Combination of RDR01752 with correctors mimicking the rescue by revertants G550E or 4RK could thus maximize rescue of F508del-CFTR.
Date of Submisson/Request
2020-04-22
Date of Acceptance
2020-06-30
Date of Publication
2020-10
Where published
Biochemical Pharmacology
Publication Identifiers
ISSN - 0006-2952
Publisher
Elsevier BV
Document Identifiers
DOI -
https://doi.org/10.1016/j.bcp.2020.114133
URL -
http://dx.doi.org/10.1016/j.bcp.2020.114133
Rankings
Web Of Science Q1 (2019) - 4.960 - PHARMACOLOGY & PHARMACY - SCIE
SCOPUS Q1 (2019) - 7.5 - Biochemistry
SCOPUS Q1 (2019) - 7.5 - Pharmacology
SCIMAGO Q1 (2019) - 1.509 - Pharmacology
Web Of Science Q1 (2020) - 5.858 - PHARMACOLOGY & PHARMACY - SCIE
SCIMAGO Q1 (2020) - 1.595 - Biochemistry
SCIMAGO Q1 (2020) - 1.595 - Pharmacology
SCOPUS Q1 (2020) - 8.4 - Pharmacology
SCOPUS Q1 (2020) - 8.4 - Biochemistry
SCIMAGO Q1 (2019) - 1.509 - Biochemistry
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