Fluorinated ΔF508-CFTR correctors and potentiators for PET imaging.

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Biophysics

Background:

• Cystic fibrosis is caused by mutations in the CFTR gene, notably the ΔF508 mutation.
• ΔF508-CFTR protein misfolding and trafficking defects lead to chloride channel dysfunction.
• Developing effective correctors and potentiators is crucial for CFTR-targeted therapies.

Purpose of the Study:

• To synthesize novel (19)F-modified bithiazole correctors and phenylglycine potentiators.
• To evaluate the functional efficacy of these fluorinated compounds on ΔF508-CFTR.
• To incorporate fluorine for potential positron emission tomography (PET) imaging applications.

Main Methods:

• Chemical synthesis of fluorinated bithiazole correctors and phenylglycine potentiators.
• Cell-based assays using human cells expressing ΔF508-CFTR.
• Utilized halide-sensitive fluorescent protein for functional assessment of chloride channel activity.

Main Results:

• Successfully synthesized (19)F-modified analogs of ΔF508-CFTR correctors and potentiators.
• Fluorinated compounds demonstrated comparable or enhanced potency in correcting and potentiating ΔF508-CFTR.
• Incorporation of fluorine did not compromise the therapeutic potential of the compounds.

Conclusions:

• Novel fluorinated compounds are effective modulators of ΔF508-CFTR.
• These compounds hold promise for both therapeutic intervention in cystic fibrosis and in vivo imaging.
• The developed molecules represent a significant advancement in CFTR-targeted drug discovery.