Small Molecule Splicing Modulators via Conformational Shift
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Solution Overview
Problem
Current therapies for modulating RNA expression, such as oligonucleotide targeting and gene therapy, face challenges in effectively addressing disease-associated alternative splicing patterns, necessitating the development of new technologies that can target and regulate splicing processes.
Innovation Solution
Development of compounds that modulate nucleic acid splicing by binding to nucleic acids or proteins involved in the splicing machinery, such as snRNPs and spliceosomes, to alter splicing events and regulate gene product levels, which can be used to prevent or treat various diseases, including proliferative, neurological, and metabolic disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If oligonucleotide targeting or gene therapy is used to modulate RNA expression, then RNA expression can be modulated, but the approach fails to effectively address disease-associated alternative splicing patterns
Solution Approach 1:
The patent employs small molecule compounds that induce conformational changes in RNA or protein-RNA complexes, altering the splicing parameters. These compounds modify the structural parameters of splicing machinery components, enabling effective targeting of alternative splicing events that oligonucleotide approaches cannot address.
Solution Approach 2:
The invention replaces the mechanical hybridization-based approach of oligonucleotides with a small molecule-based system that acts through binding-induced conformational changes. This substitution enables the compounds to access and modulate splicing regulatory elements that are inaccessible to oligonucleotide targeting.
2Adaptability or versatility
If small molecule compounds are developed to target splicing, then new therapeutic capabilities are gained, but the mechanism of action and specificity must be precisely controlled
Solution Approach 1:
The small molecule compounds act as intermediaries that bind to RNA or protein-RNA complexes and induce conformational changes. This intermediary mechanism provides precise control over splicing outcomes by translating compound binding events into specific structural changes that regulate splicing factor recruitment or release at defined splice sites.
Solution Approach 2:
The compounds exhibit local quality by targeting specific conformational states or binding interfaces within the splicing machinery. This localized action at specific molecular interfaces enables high specificity for particular splicing events while maintaining versatility across different disease-associated splicing patterns.
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 modulate splicing events, allowing for the regulation of gene product levels, thereby providing therapeutic benefits for a range of diseases by targeting specific splicing processes.
Implementation Method 1
binding to nucleic acids or proteins involved in the splicing machinery
Data Source
AI summary
The present disclosure features compounds and related compositions that, inter alia, modulate nucleic acid splicing, e.g., splicing of a pre-mRNA, as well as methods of use thereof.