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Structure-guided combination therapy to potently improve the function of mutant CFTRs

Nature Medicine volume 24, pages 1732–1742 (2018)Cite this article

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Abstract

Available corrector drugs are unable to effectively rescue the folding defects of CFTR-ΔF508 (or CFTR-F508del), the most common disease-causing mutation of the cystic fibrosis transmembrane conductance regulator, a plasma membrane (PM) anion channel, and thus to substantially ameliorate clinical phenotypes of cystic fibrosis (CF). To overcome the corrector efficacy ceiling, here we show that compounds targeting distinct structural defects of CFTR can synergistically rescue mutant expression and function at the PM. High-throughput cell-based screens and mechanistic analysis identified three small-molecule series that target defects at nucleotide-binding domain (NBD1), NBD2 and their membrane-spanning domain (MSD) interfaces. Although individually these compounds marginally improve ΔF508-CFTR folding efficiency, function and stability, their combinations lead to ~50–100% of wild-type-level correction in immortalized and primary human airway epithelia and in mouse nasal epithelia. Likewise, corrector combinations were effective against rare missense mutations in various CFTR domains, probably acting via structural allostery, suggesting a mechanistic framework for their broad application.

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Fig. 1: Identification of small-molecule ΔF508-CFTR correctors by high-throughput screening.
Fig. 2: Corrector mechanism of action.
Fig. 3: Structure-guided combination of corrector compounds restores ΔF508-CFTR biogenesis and stability.
Fig. 4: Corrector combinations rescue ΔF508-CFTR folding and functional defects.
Fig. 5: Corrector combinations rescue the ΔF508-CFTR function in human bronchial and nasal as well as mouse nasal epithelia.
Fig. 6: Rescue of rare CF folding mutants by allosteric corrector combination.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors are grateful to the individuals who volunteered to participate in this study. We thank D. C. Gruenert for the parental CFBE41o- cell line; W. E. Finkbeiner for supplying HBE cells, J. Riordan and the Cystic Fibrosis Foundation for the 660 antibody, P. Thomas for providing vectors encoding some of the CFTR2 mutants and members of the Cystic Fibrosis Folding Consortium for advice. This work was supported by Vaincre La Mucoviscidose to A.E. and I.S.-G., the Canadian Institutes of Health Research (MOP-142221 to G.L.L. and PJT-153095 to G.V., E.M., and G.L.L.), National Institute of Diabetes & Digestive & Kidney Diseases (5R01DK075302 to G.L.L.) and the Cystic Fibrosis Foundation Therapeutics to G.L.L. as well as Cystic Fibrosis Canada to G.L.L. We acknowledge the Canada Foundation for Innovation for infrastructure support: Bruker UltrafleXtreme MALDI-TOF/TOF system (grant no. 32616, awarded to G. Multhaup and G.L.L.); BIACORE T200 SPR system (grant no. 228340 awarded to G. Multhaup). R.G.A. is a recipient of the Fonds de Recherche du Québec Santé (FRQS) Doctoral Training Scholarship. G.L.L. is a Canada Research Chair.

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Authors and Affiliations

  1. Department of Physiology, McGill University, Montréal, Quebec, Canada

    Guido Veit, Haijin Xu, Radu G. Avramescu, Miklos Bagdany, Lenore K. Beitel, Ariel Roldan & Gergely L. Lukacs

  2. Institut Necker-Enfants Malades (INEM)–INSERM U1151, Paris, France

    Elise Dreano, Aleksander Edelman & Isabelle Sermet-Gaudelus

  3. SPR-MS Facility, McGill University, Montréal, Quebec, Canada

    Mark A. Hancock

  4. Genomic Institute of the Novartis Research Foundation, San Diego, CA, USA

    Cecilia Lay, Wei Li, Katelin Morin, Sandra Gao, Puiying A. Mak, Edward Ainscow, Anthony P. Orth, Peter McNamara & William G. Barnes

  5. Department of Otolaryngology - Head and Neck Surgery, McGill University, Montréal, Quebec, Canada

    Saul Frenkiel

  6. Adult Cystic Fibrosis Clinic, Montreal Chest Institute, McGill University, Montréal, Quebec, Canada

    Elias Matouk

  7. Department of Biochemistry, McGill University, Montréal, Quebec, Canada

    Gergely L. Lukacs

  8. Groupe de Recherche Axé sur la Structure des Protéines (GRASP), McGill University, Montréal, Quebec, Canada

    Gergely L. Lukacs

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  1. Guido Veit
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Contributions

The overall design of the study was by G.V., W.G.B. and G.L.L.; G.V., H.X., E.D., R.G.A., M.B., L.K.B., C.L., W.L., K.M., S.G., P.A.M., and E.A. performed experiments and analyzed the results; A.R. cloned and purified the avi-tagged NBD1 variants; M.A.H. performed the SPR studies; S.F. and E.M. collected the patient samples for HNE isolation; A.E. and I.S.-G. designed and directed the mouse studies; A.P.O., P.M. and W.G.B. designed and directed the HTS. The manuscript was primarily written by G.V. and G.L.L. with input from all authors.

Corresponding authors

Correspondence to Guido Veit or Gergely L. Lukacs.

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Competing interests

C.L., W.L., K.M., S.G., P.A.M., F.J.K., E.A., A.J.O., P.M. and W.G.B. are employees of the Genomics Institute of the Novartis Research Foundation. I.S.-G. has been principal investigator in Vertex initiated clinical trials, received a Vertex Pharmaceuticals Innovation Award and served as a scientific advisory board member for Vertex Pharmaceuticals. G.L.L. is a member of the Scientific Advisory Board of Proteostasis Therapeutics Inc. All other authors declare no competing financial or non-financial interests.

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Veit, G., Xu, H., Dreano, E. et al. Structure-guided combination therapy to potently improve the function of mutant CFTRs. Nat Med 24, 1732–1742 (2018). https://doi.org/10.1038/s41591-018-0200-x

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