Oligomeric Compounds with Modified Linkages for RNA Targeting
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Solution Overview
Problem
Current antisense compounds face challenges in achieving selective targeting and stability for therapeutic applications, with limitations in potency and specificity when interacting with RNA, particularly in maintaining function during synthesis and exposure to nucleases.
Innovation Solution
Development of oligomeric compounds with a contiguous sequence of monomer subunits linked by internucleoside linking groups, specifically incorporating Formula I linking groups that enhance selectivity and stability, allowing for improved hybridization affinity and reduced off-target effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antisense compounds are used to target RNA, then gene expression can be modulated, but selectivity and stability are insufficient leading to off-target effects and degradation
Solution Approach 1:
The patent employs composite oligomeric structures combining different nucleoside types (DNA-like 2'-deoxyribonucleosides in the gap region, RNA-like modified nucleosides in wing regions) with modified internucleoside linkages (Formula I linkages with P=O or P=S). This composite design enhances both selectivity for target RNA and resistance to degradation, resolving the contradiction between reliability and harmful effects.
Solution Approach 2:
The invention applies different structural qualities to different regions of the oligomeric compound: the gap region uses DNA-like nucleosides with specific conformational geometry for target recognition, while wing regions use RNA-like modified nucleosides for stability. The Formula I linkages are strategically placed at specific positions to enhance local stability without compromising overall selectivity.
2Stability of the object's composition
If oligomeric compounds are designed with modified internucleoside linkages to enhance stability, then resistance to nucleases improves, but synthesis complexity increases
Solution Approach 1:
The patent modifies the chemical parameters of internucleoside linkages by introducing Formula I linkages where the phosphorus atom is double-bonded to oxygen or sulfur instead of the conventional phosphodiester oxygen. This parameter change significantly enhances nuclease resistance while maintaining compatibility with standard oligonucleotide synthesis methodologies, thus improving stability without proportionally increasing synthesis complexity.
3Reliability
If high affinity hybridization is achieved through increased complementarity, then potency increases, but off-target binding may also increase reducing specificity
Solution Approach 1:
The invention creates local quality differences by using DNA-like nucleosides in the gap region for high-affinity target binding (enhancing potency) while using RNA-like modified nucleosides in the wing regions that adopt different conformational geometries (reducing off-target binding). This spatial differentiation of nucleoside properties allows high potency with improved specificity.
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
The oligomeric compounds demonstrate enhanced selectivity and potency for target RNA, providing improved stability during synthesis and exposure, leading to effective inhibition of gene expression with reduced off-target interactions.
Implementation Method 1
the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA
Implementation Method 2
providing improved stability during synthesis and exposure
Data Source
Figure 1
AI summary
The present invention provides oligomeric compounds comprising at least one neutral methoxypropyl phosphonate modified internucleoside linkage. Such oligomeric compounds have one or more improved properties such as selectivity, potency, improved toxicity profile and or improved proinflammatory profile. Such oligomeric compounds have enhanced stability to exposure to base during synthesis. 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.