CFTR Modulators Correct Protein Folding

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Solution Overview

Problem

Current treatments for CFTR-mediated diseases, such as cystic fibrosis, are limited in effectively addressing the defective protein trafficking and folding issues that lead to reduced anion transport and ion imbalances, resulting in severe respiratory and gastrointestinal complications.

Innovation Solution

Development of compounds that modulate CFTR activity by increasing or decreasing its function, specifically targeting the cystic fibrosis transmembrane conductance regulator (CFTR) to correct protein trafficking and channel activity, thereby improving anion transport across epithelial tissues.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional treatments are used for CFTR-mediated diseases, then general symptom management is provided, but defective protein trafficking and folding issues remain unaddressed

Engineering Contradiction:

Improveeffectiveness of treatmentVSAvoidability to address protein trafficking defects

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent employs small molecule compounds that bind to CFTR protein and modify its conformational parameters, enabling defective CFTR variants to achieve proper folding and trafficking to the cell membrane. This parameter change approach directly addresses the protein folding defects that conventional treatments cannot correct.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If CFTR activity is not modulated, then protein folding defects persist, but anion transport function remains insufficient

Engineering Contradiction:

Improveanion transport functionVSAvoidprotein folding accuracy

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The patent introduces small molecule compounds as intermediary substances that mediate between the defective CFTR protein and its proper conformational state. These compounds act as molecular chaperones, facilitating correct protein folding and enabling subsequent anion transport function without directly performing the transport themselves.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Object-generated harmful factors

If no specific CFTR modulators are used, then mucus accumulation continues, but current treatments cannot effectively reduce it

Engineering Contradiction:

Improvemucus accumulationVSAvoidavailability of effective treatments

Core Design Contradiction:

Object-generated harmful factorsVSEase of manufacture

Solution Approach 1:

The patent applies preliminary action by using CFTR modulators to correct protein folding and enhance CFTR function before mucus accumulation becomes severe. By improving CFTR-mediated anion transport in advance, the treatment prevents the development of thick, problematic mucus rather than attempting to clear it after formation.

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS9856248B2Modulators of cystic fibrosis transmembrane conductance regulator

Publication Date: 2018.01.02 VERTEX PHARMACEUTICALS INC

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 CFTR mediated diseases using such modulators.