CFTR Modulators Stabilize ΔF508 Protein Folding
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Solution Overview
Problem
Current treatments for cystic fibrosis and related diseases are inadequate due to the defective functioning of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, particularly the ΔF508 mutation, which impairs protein folding and trafficking, leading to reduced anion transport and severe clinical manifestations.
Innovation Solution
Development of compounds that modulate CFTR activity, specifically those with the general Formula (I), which include various substituents that stabilize and enhance the function of wild-type and mutant CFTR proteins, thereby improving anion and bicarbonate transport across epithelial membranes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CFTR modulators are used to treat cystic fibrosis, then CFTR activity and anion transport are improved, but the complexity of the treatment regimen increases
Solution Approach 1:
The patent applies parameter changes by developing compounds with specific molecular structures (Formula I) that modify the physical-chemical parameters of CFTR protein interaction. The compounds feature variable substituents (R1-R6, A, B, D groups) that can be optimized to enhance CFTR activity while improving pharmacokinetic properties for more effective treatment.
Solution Approach 2:
The invention employs composite materials by creating complex molecular structures combining multiple functional groups and substituents in a single compound framework. These composite molecular architectures enable simultaneous interaction with multiple targets or pathways involved in CFTR regulation, thereby improving therapeutic efficacy.
2Productivity
If compounds with multiple substituents are developed to enhance CFTR function, then anion transport is improved, but the manufacturing complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the complex molecule into distinct modular components (core structure with separately defined substituent groups R1-R6, A, B, D). Each module can be synthesized independently and then assembled, facilitating more manageable production processes while maintaining the complex functional requirements.
Solution Approach 2:
The invention uses local quality by allowing different regions of the molecule (specific substituent positions) to have optimized properties for different functions. Each substituent can be tailored to provide specific interactions (hydrogen bonding, hydrophobic effects, electrostatic interactions) while maintaining overall molecular stability and manufacturability.
Data Source
AI summary
The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR.