Macrocyclic CFTR Modulators for Protein Stabilization in Cystic Fibrosis

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Solution Overview

Problem

There is no cure for cystic fibrosis, and existing treatments do not effectively address the functional deficiency of the CFTR protein, leading to severe respiratory and digestive complications due to impaired chloride channel function.

Innovation Solution

Development of macrocyclic compounds that stabilize the CFTR protein, potentially correcting its misfolding and enhancing its functionality at the plasma membrane.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional treatments are used for cystic fibrosis, then current standard of care is maintained, but functional deficiency of CFTR protein is not effectively addressed

Engineering Contradiction:

ImproveCFTR protein functionalityVSAvoidrespiratory and digestive function

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent employs small molecule compounds that bind to the CFTR protein to alter its conformational parameters and stability characteristics. These compounds modify the thermodynamic and kinetic parameters of CFTR folding and gating, enabling functional rescue of mutant proteins without changing the underlying genetic sequence.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention introduces small molecule compounds as intermediary substances that mediate between the defective CFTR gene product and functional chloride channel activity. These molecules act as pharmacological chaperones and gating modulators, bridging the gap between mutant protein structure and functional requirement.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Ease of operation

If CFTR stabilizing compounds are administered, then ionic homeostasis and mucociliary clearance improve, but new compound development and therapeutic methods are still needed

Engineering Contradiction:

Improvemucociliary clearance functionVSAvoidtreatment options for CFTR mediated conditions

Core Design Contradiction:

Ease of operationVSAdaptability or versatility

Solution Approach 1:

The patent segments the CFTR modulation mechanism into distinct pharmacological actions: folding correction, stability enhancement, and gating facilitation. This segmentation allows for the development of compounds with specialized functions that can be combined in tailored therapeutic regimens for different CFTR mutation types and disease presentations.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention develops compounds with multiple mechanisms of action that can address various CFTR dysfunction types. The same class of macrocyclic compounds demonstrates efficacy across different mutation types and can be applied to both cystic fibrosis and CFTR-related disorders, providing universal therapeutic value.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS20260008785A1Macrocyclic compounds, compositions, and methods of using thereof

Publication Date: 2026.01.08 SIONNA THERAPEUTICS INC

AI summary

The present disclosure includes, among other things, CFTR modulators, pharmaceutical compositions, and methods of making and using the same.