CFTR Modulators Correcting Protein Folding Defects
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Solution Overview
Problem
Current treatments for cystic fibrosis and other diseases associated with defective CFTR protein trafficking lack effective modulators to correct protein folding and trafficking defects, leading to impaired ion and fluid transport and associated clinical symptoms.
Innovation Solution
Development of compounds that modulate ABC transporter activity, specifically targeting CFTR, to correct protein trafficking and function, thereby addressing defects in ion and fluid transport across epithelial membranes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for cystic fibrosis, then patients receive standard care, but the treatments fail to correct protein folding and trafficking defects in CFTR
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of compounds to alter their interaction with CFTR protein. Specifically, the invention uses compounds with modified core structures, substituent groups, and molecular configurations to change how these molecules bind to and modulate CFTR, thereby correcting protein folding and trafficking defects that conventional treatments cannot address
Solution Approach 2:
The patent employs intermediary compounds that act as molecular mediators between the cellular environment and the defective CFTR protein. These compound modulators serve as intermediaries that facilitate proper protein folding, enhance protein stability, and improve trafficking to the cell membrane, thereby bridging the gap between the defective protein and functional restoration
2Productivity
If CFTR activity is enhanced to improve ion and fluid transport, then transport function improves, but the complexity of modulator compounds increases
Solution Approach 1:
The patent applies segmentation by dividing the modulator compound into distinct functional modules: a core structure, substituent groups at specific positions, and stereocenter configurations. Each segment contributes a specific function—such as binding affinity, selectivity, or pharmacokinetic properties—allowing the overall molecule to achieve high CFTR modulation efficiency while maintaining a systematic, modular design that manages molecular complexity
Solution Approach 2:
The patent implements local quality by introducing specific substituent groups at particular positions on the core structure, and by controlling stereocenter configurations. These localized modifications enhance specific interactions with CFTR at particular binding sites, thereby improving ion and fluid transport efficiency without requiring uniform complexity throughout the entire molecular structure
Data Source
AI summary
The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.