New insights into structure and function of bis-phosphinic acid derivatives and implications for CFTR modulation.

Bronchi / drug effects Cells, Cultured Cystic Fibrosis / drug therapy Cystic Fibrosis Transmembrane Conductance Regulator / genetics Homozygote Humans Molecular Docking Simulation Mutation Nasal Cavity / drug effects Phosphinic Acids / chemistry

Journal

Scientific reports

ISSN: 2045-2322

Titre abrégé: Sci Rep

Pays: England

ID NLM: 101563288

Informations de publication

Date de publication:
25 03 2021

Historique:

received: 15 12 2019

accepted: 18 01 2021

entrez: 26 3 2021

pubmed: 27 3 2021

medline: 21 10 2021

Statut: epublish

Résumé

C407 is a compound that corrects the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein carrying the p.Phe508del (F508del) mutation. We investigated the corrector effect of c407 and its derivatives on F508del-CFTR protein. Molecular docking and dynamics simulations combined with site-directed mutagenesis suggested that c407 stabilizes the F508del-Nucleotide Binding Domain 1 (NBD1) during the co-translational folding process by occupying the position of the p.Phe1068 side chain located at the fourth intracellular loop (ICL4). After CFTR domains assembly, c407 occupies the position of the missing p.Phe508 side chain. C407 alone or in combination with the F508del-CFTR corrector VX-809, increased CFTR activity in cell lines but not in primary respiratory cells carrying the F508del mutation. A structure-based approach resulted in the synthesis of an extended c407 analog G1, designed to improve the interaction with ICL4. G1 significantly increased CFTR activity and response to VX-809 in primary nasal cells of F508del homozygous patients. Our data demonstrate that in-silico optimized c407 derivative G1 acts by a mechanism different from the reference VX-809 corrector and provide insights into its possible molecular mode of action. These results pave the way for novel strategies aiming to optimize the flawed ICL4-NBD1 interface.

Identifiants

DOI: 10.1038/s41598-021-83240-x PMID: 33767236 PMC: PMC7994384

pubmed: 33767236

doi: 10.1038/s41598-021-83240-x

pii: 10.1038/s41598-021-83240-x

pmc: PMC7994384

doi:

Substances chimiques

CFTR protein, human 0

Phosphinic Acids 0

Cystic Fibrosis Transmembrane Conductance Regulator 126880-72-6

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

6842

Commentaires et corrections

Type : ErratumIn

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