Stabilizing TTR Tetramers to Inhibit Amyloid Formation
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Solution Overview
Problem
Current therapies lack effective small-molecule solutions for targeting protein-protein interactions (PPIs) involved in protein misfolding and amyloid formation, particularly in diseases like familial amyloid polyneuropathy and senile systemic amyloidosis, due to the large and complex interfaces of these interactions, making them challenging to inhibit with small molecules.
Innovation Solution
Development of compounds that bind to the TTR tetramer, specifically stabilizing it to prevent dissociation and subsequent amyloid formation, and heterobifunctional compounds that disrupt PPIs by recruiting targeting moieties via linkers to specific proteins, thereby inhibiting disease-associated protein interactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Device complexity
If small molecules are used to inhibit protein-protein interactions, then the complexity of the intervention is reduced, but the ability to effectively target large and complex PPI interfaces is insufficient
Solution Approach 1:
The patent employs stabilizing compounds as intermediaries that bind to TTR tetramers and prevent their dissociation into amyloidogenic monomers. These small-molecule intermediaries indirectly inhibit the protein-protein interactions leading to amyloid formation without needing to directly block the large PPI interfaces, thus resolving the contradiction between simplicity and effectiveness.
Solution Approach 2:
The invention changes the physical-chemical parameters of the TTR protein by introducing small-molecule binders that alter the stability, solubility, and conformational equilibrium of TTR tetramers. This parameter change approach allows small molecules to effectively influence the amyloidogenesis process without directly engaging the complex PPI interfaces.
2Stability of the object's composition
If TTR tetramers are stabilized to prevent dissociation, then amyloid formation is reduced, but the therapeutic intervention complexity increases
Solution Approach 1:
The stabilizing compounds enable TTR tetramers to maintain their stable, non-amyloidogenic state through self-stabilization mechanisms. The small molecules bind to TTR and enhance the tetramer's inherent stability, allowing the protein to resist dissociation and amyloid formation on its own, thus reducing the overall therapeutic complexity while achieving the desired stability enhancement.
3Reliability
If heterobifunctional compounds are used to disrupt PPIs, then the ability to inhibit disease-associated interactions is improved, but the manufacturing complexity increases
Solution Approach 1:
The heterobifunctional compounds are designed as segmented molecules with distinct functional domains: a TTR-binding moiety, a linker, and a targeting moiety. This segmentation allows each component to be optimized independently for its specific function, simplifying the manufacturing process while maintaining the ability to effectively disrupt disease-associated PPIs through the coordinated action of the segmented structure.
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
The compounds effectively increase the stability of TTR tetramers, reducing amyloid formation and associated cell dysfunction, and can be administered to prevent or treat various amyloid-related diseases by stabilizing TTR in bodily fluids and tissues, including the central nervous system and heart.
Implementation Method 1
Compounds and compositions that bind and stabilize transthyretin
Implementation Method 2
increasing the stability of proteins, particularly proteins that may misfold and form aggregates
Data Source
AI summary
Disclosed herein are compounds and compositions thereof which find use in increasing stability of proteins particularly proteins that tend to misfold and form aggregates. Also provided herein are methods for using these compounds and compositions for increasing stability of proteins and thereby decreasing aggregate formation by these proteins. Also disclosed herein are heterobifunctional compounds that include a TTR binding compound connected to a targeting moiety via a linker, for use in disrupting PPIs of a target protein.