CFTR Modulators Correcting Protein Folding Defects
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Solution Overview
Problem
Current treatments for ABC transporter-mediated diseases, such as cystic fibrosis, are limited in effectively modulating the activity of ABC transporters like CFTR, particularly in correcting the folding defects that lead to protein mislocalization and reduced chloride transport.
Innovation Solution
The use of specific compounds, such as those with the formula I or I′, which modulate ABC transporter activity by contacting the transporters with pharmaceutically acceptable salts, facilitating the correct trafficking and density of CFTR in the plasma membrane, thereby enhancing chloride transport.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for ABC transporter-mediated diseases, then disease management is maintained, but the ability to effectively modulate ABC transporter activity and correct folding defects is insufficient
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of modulator compounds (changing molecular parameters) to achieve different levels of transporter modulation. The compounds of formula I and I' represent specific parameter configurations that enhance binding affinity and modulatory effectiveness, allowing tailored treatment approaches for different ABC transporter conditions.
Solution Approach 2:
The patent uses small molecule compounds as intermediaries that bind to ABC transporters and mediate the modulation of their activity. These compound intermediaries facilitate the correction of folding defects and enhance transporter function without directly altering the transporter gene or protein structure, providing a pharmacological bridge between treatment and therapeutic effect.
2Productivity
If compounds of formula I or I' are used to increase CFTR density in plasma membrane, then chloride transport is improved, but the complexity of pharmacological intervention increases
Solution Approach 1:
The patent employs preliminary action by using compounds that pre-correct folding defects and facilitate proper CFTR trafficking to the plasma membrane before chloride transport can occur. The modulators act upstream in the pathological cascade, preparing the transporter for functional activity rather than directly stimulating transport or compensating for its absence.
Solution Approach 2:
The patent changes the concentration parameter of CFTR in the plasma membrane through pharmacological intervention. By increasing the density of functional CFTR proteins at the membrane surface, the treatment directly enhances chloride transport capacity without requiring complex multi-drug regimens or invasive procedures.
3Manufacturing precision
If protein folding defects are not corrected, then CFTR mislocalization occurs, but the mechanisms to correct these folding defects are limited
Solution Approach 1:
The patent introduces small molecule compounds as intermediaries that bind to nascent or misfolded CFTR proteins and facilitate proper folding. These molecular chaperone-like compounds act as intermediaries between the defective protein and the cellular folding machinery, stabilizing intermediate folding states and guiding correct conformation without requiring genetic modification or complex cellular reprogramming.
Solution Approach 2:
The patent changes the conformational parameters of CFTR proteins by providing compounds that stabilize correct folding states. The modulators alter the energy landscape of protein folding, shifting the equilibrium toward properly folded, functional conformations and enabling correct localization to the plasma membrane.
Data Source
AI summary
The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including CF Transmembrane Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.