CFTR Modulators Correct Protein Folding via Parameter Changes
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Solution Overview
Problem
Current treatments for ABC transporter-mediated diseases, such as cystic fibrosis, lack effective modulators to address defective protein trafficking and ion transport imbalances, leading to severe symptoms and complications.
Innovation Solution
Development of compounds that modulate ABC transporter activity, specifically targeting CFTR, to enhance anion secretion and correct protein folding defects, thereby improving ion and fluid transport across epithelial tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for ABC transporter-mediated diseases are used, then disease management is maintained, but effective modulators to address defective protein trafficking and ion transport imbalances are lacking
Solution Approach 1:
The patent modifies the chemical structure of CFTR modulators by changing parameters such as the introduction of a carbonyl group at the 6-position of the pyridine ring and varying substituent groups (R1-R4, n values) to enhance efficacy against defective protein trafficking and ion transport imbalances
Solution Approach 2:
The invention creates composite chemical structures combining pyridine core with various substituent groups (aryl, heteroaryl, cycloaliphatic, etc.) to develop multi-functional modulators that can address multiple aspects of CFTR deficiency simultaneously
2Productivity
If CFTR activity is enhanced to improve ion and fluid transport, then disease symptoms are reduced, but protein folding defects may persist
Solution Approach 1:
The patent introduces intermediary substances (chemical modulators) that mediate between the defective CFTR protein and the physiological environment, facilitating proper protein folding and function while improving ion and fluid transport across epithelial tissues
3Reliability
If modulators are developed to correct protein folding defects, then CFTR activity improves, but treatment complexity increases
Solution Approach 1:
The patent segments the complex CFTR protein into functional domains (nucleotide binding domains, transmembrane domains, regulatory domains) and develops modulators that specifically target each domain's requirements for proper folding and function, simplifying the treatment approach
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These compounds effectively treat or alleviate the severity of various diseases by enhancing CFTR activity, improving ion and fluid transport, and reducing disease symptoms associated with defective protein trafficking.
Implementation Method 1
ABC transporters are homologous membrane proteins that bind and use cellular adenosine triphosphate (ATP) for their specific activities
Implementation Method 2
CFTR is a cAMP/ATP-mediated anion channel that regulates anion flux across the membrane
Implementation Method 3
CFTR is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane
Data Source
AI summary
Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention.