Stereodefined Phosphorothioate Oligonucleotide Toxicity Reduction
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current antisense oligonucleotides face challenges with toxicity, particularly hepatotoxicity and nephrotoxicity, which limits their therapeutic potential due to the susceptibility of certain stereoisomers to rapid degradation and immune stimulation, leading to short-term effects and increased risk of adverse reactions.
Innovation Solution
A method is developed to create and screen libraries of stereodefined phosphorothioate oligonucleotide variants, retaining the core nucleobase sequence, to identify variants with reduced toxicity through in vitro or in vivo screening, allowing for the selection and manufacturing of oligonucleotides with enhanced stability and reduced side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If stereodefined phosphorothioate oligonucleotide variants are created and screened, then toxicity is reduced, but the complexity of the synthesis and characterization increases
Solution Approach 1:
The patent segments the phosphorothioate linkages into individual stereodefined positions, allowing systematic creation of variants with specific stereochemistry at each position. This segmentation enables targeted modification of toxic positions while maintaining overall oligonucleotide structure, reducing toxicity through precise stereochemical control rather than comprehensive redesign
Solution Approach 2:
The patent systematically varies the stereochemical parameters (Rp/Sp configuration) at specific phosphorothioate positions to identify configurations that reduce toxicity. By changing these physical-chemical parameters while maintaining the core oligonucleotide structure, the invention achieves reduced hepatotoxicity and nephrotoxicity without requiring complete structural redesign
2Object-affected harmful factors
If stereodefined variants are screened in vitro or in vivo, then variants with reduced toxicity are identified, but the time and resources required for screening increase
Solution Approach 1:
The patent performs preliminary in silico modeling and in vitro screening of stereodefined variants before proceeding to in vivo studies. This staged approach allows early identification of promising variants with reduced toxicity, filtering out ineffective configurations before committing significant resources to animal studies, thereby reducing overall screening time
Solution Approach 2:
The patent focuses screening efforts on specific positions within the oligonucleotide where stereodefined variants are most likely to reduce toxicity based on structural analysis. Rather than screening all possible variants uniformly, the invention concentrates resources on locally optimized positions, reducing the total number of variants that require extensive screening
Data Source
AI summary
The invention relates to a method of identifying stereodefined phosphorothioate oligonucleotide variants with reduced toxicity by creating and screening libraries of stereodefined chiral phosphorothioate variants for compounds with reduced toxicity, either in vitro or in vivo.