ArticleProtein science : a publication of the Protein Society2016
Binding screen for cystic fibrosis transmembrane conductance regulator correctors finds new chemical matter and yields insights into cystic fibrosis therapeutic strategy.
Article in Protein science : a publication of the Protein Society, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Inhibitory targeting cGAS-STING-TBK1 axis: Emerging strategies for autoimmune diseases therapy.Frontiers in immunology · 2022Review
- Pharmacological chaperones improve intra-domain stability and inter-domain assembly via distinct binding sites to rescue misfolded CFTR.Cellular and molecular life sciences : CMLS · 2021Article
- Stability Prediction for Mutations in the Cytosolic Domains of Cystic Fibrosis Transmembrane Conductance Regulator.Journal of chemical information and modeling · 2021Article
- New insights into structure and function of bis-phosphinic acid derivatives and implications for CFTR modulation.Scientific reports · 2021Article
- Comprehensive Analysis of Chemical Structures That Have Been Tested as CFTR Activating Substances in a Publicly Available Database CandActCFTR.Frontiers in pharmacology · 2021Article
- Molecular Docking and QSAR Studies as Computational Tools Exploring the Rescue Ability of F508del CFTR Correctors.International journal of molecular sciences · 2020Article
- Recent Strategic Advances in CFTR Drug Discovery: An Overview.International journal of molecular sciences · 2020Review
- A simple model for determining affinity from irreversible thermal shifts.Protein science : a publication of the Protein Society · 2019Article
- Domain-interface dynamics of CFTR revealed by stabilizing nanobodies.Nature communications · 2019Article
- Differential Scanning Fluorimetry and Hydrogen Deuterium Exchange Mass Spectrometry to Monitor the Conformational Dynamics of NBD1 in Cystic Fibrosis.Methods in molecular biology (Clifton, N.J.) · 2019Article
- Ligand binding to a remote site thermodynamically corrects the F508del mutation in the human cystic fibrosis transmembrane conductance regulator.The Journal of biological chemistry · 2018Article
- Structure-guided combination therapy to potently improve the function of mutant CFTRs.Nature medicine · 2018Article
- ΔF508-CFTR Modulator Screen Based on Cell Surface Targeting of a Chimeric Nucleotide Binding Domain 1 Reporter.SLAS discovery : advancing life sciences R & D · 2018Article
- The catalytic mechanism of cyclic GMP-AMP synthase (cGAS) and implications for innate immunity and inhibition.Protein science : a publication of the Protein Society · 2017Article
- Discovery of PF-06928215 as a high affinity inhibitor of cGAS enabled by a novel fluorescence polarization assay.PloS one · 2017Article
- Molecular modelling and molecular dynamics of CFTR.Cellular and molecular life sciences : CMLS · 2017Review
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Authors and funding
9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The most common mutation in cystic fibrosis (CF) patients is deletion of F508 (ΔF508) in the first nucleotide binding domain (NBD1) of the CF transmembrane conductance regulator (CFTR). ΔF508 causes a decrease in the trafficking of CFTR to the cell surface and reduces the thermal stability of isolated NBD1; it is well established that both of these effects can be rescued by additional revertant mutations in NBD1. The current paradigm in CF small molecule drug discovery is that, like revertant mutations, a path may exist to ΔF508 CFTR correction through a small molecule chaperone binding to NBD1. We, therefore, set out to find small molecule binders of NBD1 and test whether it is possible to develop these molecules into potent binders that increase CFTR trafficking in CF-patient-derived human bronchial epithelial cells. Several fragments were identified that bind NBD1 at either the CFFT-001 site or the BIA site. However, repeated attempts to improve the affinity of these fragments resulted in only modest gains. Although these results cannot prove that there is no possibility of finding a high-affinity small molecule binder of NBD1, they are discouraging and lead us to hypothesize that the nature of these two binding sites, and isolated NBD1 itself, may not contain the features needed to build high-affinity interactions. Future work in this area may, therefore, require constructs including other domains of CFTR in addition to NBD1, if high-affinity small molecule binding is to be achieved.
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