Chiral Oligonucleotide Backbones for Nuclease Stability
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Solution Overview
Problem
Naturally occurring nucleic acids are unstable against extra- and intracellular nucleases and exhibit poor cell penetration and distribution, limiting their therapeutic efficacy, and existing oligonucleotides do not effectively address stability and activity issues.
Innovation Solution
Development of stereorandom oligonucleotide preparations with optimized patterns of backbone chiral centers to enhance stability and biological activity, including specific stereoisomers that improve cleavage selectivity and minimize off-target effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If naturally occurring nucleic acids are used for therapeutics, then they can perform basic biological functions, but they exhibit poor stability against nucleases and poor cell penetration
Solution Approach 1:
The patent applies parameter changes by modifying the stereochemical configuration at phosphorus chiral centers in the oligonucleotide backbone. By controlling the stereoisomeric composition (e.g., using all-R, all-S, or specific diastereomeric patterns) and adjusting the pattern of backbone linkages, the patent enhances resistance to nuclease degradation while maintaining biological activity. This resolves the contradiction by changing the chemical parameters of the oligonucleotide structure without fundamentally altering its nucleic acid nature.
2Adaptability or versatility
If stereorandom oligonucleotide preparations are used, then they contain multiple stereoisomers, but individual stereoisomers with optimized stability and activity are not obtained
Solution Approach 1:
The patent applies local quality by focusing on specific local stereoisomeric configurations at particular phosphorus chiral centers within the oligonucleotide chain. Rather than requiring complete control of all stereocenters, the invention identifies and optimizes specific patterns (e.g., all-R, all-S, or alternating R-S patterns) at key positions. This allows production of substantially pure preparations of specific stereoisomers with optimized properties, resolving the contradiction between diversity and precision by applying selective quality control to critical local regions.
3Reliability
If modified backbone linkages or bases are used to improve stability, then stability increases, but the complexity of the oligonucleotide structure increases
Solution Approach 1:
The patent applies asymmetry by exploiting the chiral nature of phosphorus atoms in the oligonucleotide backbone. Instead of using symmetric modifications or complex structural changes, the invention focuses on establishing specific asymmetric configurations at phosphorus chiral centers. By controlling the stereochemistry to produce enantiomerically pure or enriched oligonucleotides (all-R, all-S, or specific diastereomers), the patent achieves enhanced stability through natural chiral recognition by nucleases, which typically process chiral substrates with preference, without introducing complex chemical modifications to the backbone linkages or bases.
Data Source
AI summary
The present invention relates to chirally controlled oligonucleotides of select designs, chirally controlled oligonucleotide compositions, and methods of making and using the same. In some embodiments, a provided chirally controlled oligonucleotide composition provides different cleavage patterns of a nucleic acid polymer than a reference oligonucleotide composition. In some embodiments, a provided chirally controlled oligonucleotide composition provides single site cleavage within a complementary sequence of a nucleic acid polymer.