Bicyclic Gapmer Oligonucleotides for Specific Nucleic Acid Binding
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Solution Overview
Problem
Existing antisense compounds face challenges in effectively modulating target nucleic acids, particularly in terms of binding efficiency and specificity, which affects their therapeutic potential.
Innovation Solution
Development of oligonucleotides comprising a gapmer region with 5′- and 3′-wings, incorporating bicyclic and 2′-substituted nucleosides, which enhance binding affinity and specificity to target nucleic acids.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antisense compounds are used, then binding to target nucleic acids occurs, but binding efficiency and specificity are insufficient
Solution Approach 1:
The patent applies local quality by incorporating bicyclic nucleosides at specific positions within the oligonucleotide sequence, particularly in the 5'-wing and gapmer region. These bicyclic nucleosides provide enhanced binding affinity and specificity to target nucleic acids compared to conventional nucleosides, directly addressing the binding efficiency problem while maintaining therapeutic potential.
Solution Approach 2:
The patent creates a composite oligonucleotide structure combining different nucleoside types: bicyclic nucleosides in the 5'-wing, 2'-substituted nucleosides in the gapmer region, and conventional nucleosides in the 3'-wing. This composite approach leverages the advantages of each component to achieve superior binding efficiency and specificity while preserving therapeutic activity.
2Reliability
If oligonucleotides with bicyclic and 2′-substituted nucleosides are incorporated, then binding affinity and specificity are enhanced, but structural complexity increases
Solution Approach 1:
The patent segments the oligonucleotide into distinct functional regions: a 5'-wing containing bicyclic nucleosides for initial binding, a gapmer region with 2'-substituted nucleosides for enhanced specificity, and a 3'-wing with conventional nucleosides for stability. This segmentation allows each region to perform its specific function while managing overall structural complexity.
Solution Approach 2:
Rather than uniformly modifying the entire oligonucleotide, the patent applies local quality by placing bicyclic nucleosides specifically in the 5'-wing and 2'-substituted nucleosides in the gapmer region. This targeted modification enhances binding affinity and specificity at critical locations while avoiding unnecessary complexity throughout the entire structure.
Data Source
AI summary
The present invention provides oligomeric compounds. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount activity or expression of the target nucleic acid in a cell.