Journal
NATURE MEDICINE
Volume 24, Issue 11, Pages 1732-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-018-0200-x
Keywords
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Funding
- Vaincre La Mucoviscidose
- Canadian Institutes of Health Research [MOP-142221, PJT-153095]
- National Institute of Diabetes AMP
- Digestive AMP
- Kidney Diseases [5R01DK075302]
- Cystic Fibrosis Foundation Therapeutics
- Cystic Fibrosis Canada
- Canada Foundation for Innovation [32616, 228340]
- Fonds de Recherche du Quebec Sante (FRQS) Doctoral Training Scholarship
- BIACORE T200 SPR system [228340]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK075302] Funding Source: NIH RePORTER
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Available corrector drugs are unable to effectively rescue the folding defects of CFTR-Delta F508 (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 Delta F508-CFTR folding efficiency, function and stability, their combinations lead to similar 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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