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

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Cystic fibrosis transmembrane conductance regulator (CFTR) protein mutations cause cystic fibrosis (CF).
• The most common mutation, CFTR-ΔF508, leads to protein misfolding and dysfunction.
• Current corrector drugs have limited efficacy in rescuing CFTR-ΔF508 folding and function.

Purpose of the Study:

• To develop novel therapeutic strategies to overcome the limitations of existing CFTR corrector drugs.
• To identify compounds that can synergistically improve the expression and function of mutant CFTR at the plasma membrane.

Main Methods:

• High-throughput cell-based screening to identify small-molecule series targeting distinct CFTR structural defects.
• Mechanistic analysis of compounds targeting nucleotide-binding domain 1 (NBD1), NBD2, and membrane-spanning domain (MSD) interfaces.
• Assessment of combined compound efficacy in immortalized and primary human airway epithelia and mouse nasal epithelia.

Main Results:

• Three small-molecule series were identified, targeting NBD1, NBD2, and MSD interfaces.
• Individual compounds showed marginal improvement in ΔF508-CFTR folding, function, and stability.
• Combinations of these compounds achieved 50-100% of wild-type-level correction in various epithelial models.
• Corrector combinations also demonstrated efficacy against rare CFTR missense mutations.

Conclusions:

• Synergistic drug combinations targeting distinct CFTR structural defects can effectively rescue mutant CFTR expression and function.
• This combinatorial approach represents a significant advancement in treating cystic fibrosis, particularly for the common F508del mutation.
• The findings suggest a broad applicability of this strategy for various CFTR mutations through structural allostery.