New insights into structure and function of bis-phosphinic acid derivatives and implications for CFTR modulation
Abstract 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...
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Nature Portfolio
2021
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oai:doaj.org-article:c78c19594a5d4a81b0e0face0bb082c42021-12-02T16:36:12ZNew insights into structure and function of bis-phosphinic acid derivatives and implications for CFTR modulation10.1038/s41598-021-83240-x2045-2322https://doaj.org/article/c78c19594a5d4a81b0e0face0bb082c42021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83240-xhttps://doaj.org/toc/2045-2322Abstract 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.Sara BitamAhmad ElbahnsiGeordie CresteIwona PrankeBenoit ChevalierFarouk BerhalBrice HoffmannNathalie ServelDanielle TondelierAurelie HattonChristelle MoquereauMélanie Faria Da CunhaAlexandra PastorAgathe LepissierAlexandre HinzpeterJean-Paul MornonGuillaume PrestatAleksander EdelmanIsabelle CallebautChristine Gravier-PelletierIsabelle Sermet-GaudelusNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021) |
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DOAJ |
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Medicine R Science Q |
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Medicine R Science Q Sara Bitam Ahmad Elbahnsi Geordie Creste Iwona Pranke Benoit Chevalier Farouk Berhal Brice Hoffmann Nathalie Servel Danielle Tondelier Aurelie Hatton Christelle Moquereau Mélanie Faria Da Cunha Alexandra Pastor Agathe Lepissier Alexandre Hinzpeter Jean-Paul Mornon Guillaume Prestat Aleksander Edelman Isabelle Callebaut Christine Gravier-Pelletier Isabelle Sermet-Gaudelus New insights into structure and function of bis-phosphinic acid derivatives and implications for CFTR modulation |
| description |
Abstract 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. |
| format |
article |
| author |
Sara Bitam Ahmad Elbahnsi Geordie Creste Iwona Pranke Benoit Chevalier Farouk Berhal Brice Hoffmann Nathalie Servel Danielle Tondelier Aurelie Hatton Christelle Moquereau Mélanie Faria Da Cunha Alexandra Pastor Agathe Lepissier Alexandre Hinzpeter Jean-Paul Mornon Guillaume Prestat Aleksander Edelman Isabelle Callebaut Christine Gravier-Pelletier Isabelle Sermet-Gaudelus |
| author_facet |
Sara Bitam Ahmad Elbahnsi Geordie Creste Iwona Pranke Benoit Chevalier Farouk Berhal Brice Hoffmann Nathalie Servel Danielle Tondelier Aurelie Hatton Christelle Moquereau Mélanie Faria Da Cunha Alexandra Pastor Agathe Lepissier Alexandre Hinzpeter Jean-Paul Mornon Guillaume Prestat Aleksander Edelman Isabelle Callebaut Christine Gravier-Pelletier Isabelle Sermet-Gaudelus |
| author_sort |
Sara Bitam |
| title |
New insights into structure and function of bis-phosphinic acid derivatives and implications for CFTR modulation |
| title_short |
New insights into structure and function of bis-phosphinic acid derivatives and implications for CFTR modulation |
| title_full |
New insights into structure and function of bis-phosphinic acid derivatives and implications for CFTR modulation |
| title_fullStr |
New insights into structure and function of bis-phosphinic acid derivatives and implications for CFTR modulation |
| title_full_unstemmed |
New insights into structure and function of bis-phosphinic acid derivatives and implications for CFTR modulation |
| title_sort |
new insights into structure and function of bis-phosphinic acid derivatives and implications for cftr modulation |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/c78c19594a5d4a81b0e0face0bb082c4 |
| work_keys_str_mv |
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