Small Molecule Splicing Modulators Overcoming Pre-mRNA Steric Hindrance
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Solution Overview
Problem
Current therapeutic approaches for controlling mRNA expression, such as gene therapy and oligonucleotide technologies, face challenges including unfavorable pharmacokinetics, lack of oral bioavailability, and difficulty penetrating the blood-brain barrier, as well as structural and steric hindrances due to the complex secondary and tertiary structures of pre-mRNA, limiting their effectiveness in treating RNA-mediated diseases.
Innovation Solution
Development of small molecule splicing modulators (SMSMs) that can modulate splicing processes without the limitations faced by oligonucleotides, by interacting with pre-mRNA in a way that bypasses structural complexities and enhances delivery and functionality.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If oligonucleotide therapies are used to modulate mRNA expression, then specificity to target sequences can be achieved, but pharmacokinetics are unfavorable and oral bioavailability is lacking
Solution Approach 1:
The patent replaces the mechanical/chemical hybridization system of oligonucleotides with a small molecule system that uses non-canonical binding mechanisms. The small molecule compounds bind to pre-mRNA through stacking interactions and hydrogen bonding rather than canonical base pairing, thereby achieving target modulation while improving pharmacokinetic properties and oral bioavailability.
Solution Approach 2:
The patent changes the fundamental binding parameters from canonical base pairing (oligonucleotides) to non-canonical interactions including base stacking and hydrogen bonding (small molecules). This parameter change enables the therapeutic agent to maintain target specificity while achieving favorable pharmacokinetics and oral bioavailability.
2Measurement precision
If oligonucleotides are used to anneal to target pre-mRNA, then base pairing specificity is achieved, but structural and steric hindrances from pre-mRNA complexity limit effectiveness
Solution Approach 1:
The patent substitutes the rigid canonical base pairing mechanism with a flexible small molecule binding system that utilizes stacking interactions and hydrogen bonding. This alternative mechanism is less susceptible to the structural and steric hindrances posed by pre-mRNA's complex secondary and tertiary structures, while maintaining binding specificity.
Solution Approach 2:
The small molecule compounds exhibit dynamic binding characteristics that allow them to adapt to the complex three-dimensional structure of pre-mRNA. Unlike rigid oligonucleotides, the small molecules can conformationally adjust to bind effectively despite structural obstacles, thereby overcoming steric hindrances.
3Reliability
If small molecule splicing modulators are developed, then delivery and oral bioavailability are improved, but interaction with complex pre-mRNA structures must be achieved
Solution Approach 1:
The patent employs small molecule compounds that use non-canonical binding mechanisms (stacking and hydrogen bonding) instead of canonical base pairing. This substitution enables improved delivery and oral bioavailability while maintaining the ability to specifically interact with complex pre-mRNA structures through alternative molecular recognition pathways.
Data Source
AI summary
Described herein are small molecule splicing modulator compounds that modulate splicing of mRNA, such as pre-mRNA, encoded by genes, pharmaceutical compositions comprising the same, and methods of use of the small molecule splicing modulator compounds for modulating splicing and treating diseases and conditions.