Silicon-Modified CFTR Modulators for Protein Stability
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Solution Overview
Problem
Current treatments for cystic fibrosis and other conditions related to CFTR dysfunction are inadequate in effectively modulating cystic fibrosis transmembrane conductance regulator (CFTR) activity, leading to imbalances in protein homeostasis and resulting in respiratory and other organ dysfunctions.
Innovation Solution
Development of compounds with silicon-modified N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide and its pharmaceutically acceptable salts, which enhance CFTR activity by replacing carbon atoms with silicon, optionally combined with additional CFTR modulators.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for cystic fibrosis, then CFTR activity remains insufficient, but replacing carbon atoms with silicon in the compound structure increases CFTR activity and protein stability
Solution Approach 1:
The patent applies parameter changes by substituting carbon atoms with silicon atoms in the chemical structure of CFTR modulator compounds. This atomic substitution modifies the physical and chemical parameters of the molecule, enhancing its ability to stabilize CFTR protein and improve channel activity while addressing the insufficiency of current treatments
Solution Approach 2:
The invention creates composite chemical structures by combining silicon-modified molecular frameworks with pharmacophore groups. These composite compounds integrate the stabilizing effects of silicon substitution with the CFTR-modulating properties of the core molecular structure, achieving enhanced therapeutic efficacy
2Stability of the object's composition
If protein homeostasis is disrupted due to CFTR dysfunction, then respiratory and organ dysfunctions occur, but silicon-modified compounds improve ion transport and protein stability
Solution Approach 1:
The silicon-modified compounds act as intermediaries that bridge the gap between disrupted protein homeostasis and functional CFTR activity. These compounds bind to CFTR and stabilize its folded conformation, mediating the restoration of proper protein function and preventing the downstream harmful effects including respiratory dysfunction
Solution Approach 2:
The invention provides beforehand cushioning by stabilizing CFTR protein before it can be degraded or misfolded. The silicon-modified compounds prevent protein misfolding and aggregation proactively, cushioning against the development of respiratory and organ dysfunctions before they occur
Data Source
AI summary
The present disclosure is directed to disclosed compounds that modulate e.g., address underlying defects in cellular processing of CFTR activity.