Modified Oligonucleotides with Carbon-Based Linkages for Metabolic Stability
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Solution Overview
Problem
Current RNA-based therapeutic strategies face challenges due to toxicity issues from non-specific protein binding and incompatibility with biological machineries, particularly with Argonaute proteins and CRISPR systems, limiting the use of backbone modifications like Phosphorothioate, Peptide Nucleic Acid, and Phosphorodiamidate Morpholino Oligonucleotides.
Innovation Solution
Development of modified oligonucleotides with specific intersubunit linkages, such as those described in Formula I, which substitute the bridging oxygen of the phosphodiester bond with organic functional groups, enhancing compatibility with RNA-binding machineries while minimizing toxic non-specific binding to proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If Phosphorothioate (PS) modification is used to achieve metabolic stability, then stability is improved, but toxicity increases due to non-specific binding to proteins
Solution Approach 1:
The patent changes the chemical parameters of the backbone modification by substituting the bridging oxygen with carbon atoms (forming C-C, C-O, or C-N bonds) instead of using traditional phosphorothioate modifications. This parameter change maintains metabolic stability while reducing non-specific protein binding toxicity by altering the chemical properties of the backbone without compromising the essential stability function.
Solution Approach 2:
The patent creates composite backbone structures combining carbon-based linkages with modified nucleotide units. These composite materials integrate the stability-providing carbon backbone with the RNA-compatible modified nucleotides, achieving both metabolic stability and reduced toxic non-specific binding through the synergistic combination of different chemical components.
2Stability of the object's composition
If Peptide Nucleic Acid (PNA) or Phosphorodiamidate Morpholino Oligonucleotide (PMO) modifications are used to achieve metabolic stability, then stability is improved, but compatibility with RNA-binding biological machineries deteriorates
Solution Approach 1:
The patent changes the backbone composition parameters by incorporating carbon-based linkages (C-C, C-O, C-N bonds) that closely resemble natural RNA structures, unlike PNA's peptide backbone or PMO's morpholino structure. This parameter change enables compatibility with RNA-binding biological machineries such as Argonaute proteins and RNaseH while maintaining metabolic stability through the chemically stable carbon-based backbone.
Solution Approach 2:
The patent applies local quality by modifying only the backbone linkage regions with carbon-based connections while keeping the nucleotide bases and sugar moieties similar to natural RNA. This localized modification approach maintains compatibility with RNA-binding proteins that recognize specific nucleotide structures, while the modified backbone regions provide enhanced metabolic stability without disrupting overall RNA structure recognition.
3Adaptability or versatility
If traditional phosphodiester bonds are used to maintain RNA structure recognition, then compatibility with biological machineries is improved, but metabolic stability deteriorates
Solution Approach 1:
The patent changes the chemical parameter of the backbone bonds by replacing the labile phosphodiester linkage (P-O-P) with metabolically stable carbon-based bonds (C-C, C-O, or C-N). This parameter change confers resistance to nucleolytic degradation and enzymatic cleavage, providing metabolic stability while maintaining the overall structural features necessary for RNA-binding machinery recognition.
Solution Approach 2:
The carbon-based backbone linkages act as intermediary structures that bridge the gap between the need for metabolic stability and compatibility with RNA-binding proteins. These intermediary linkages provide the structural framework that maintains RNA-like geometry for protein recognition while introducing metabolic stability through chemically inert carbon bonds, mediating between the two opposing requirements.
Data Source
AI summary
This disclosure relates to novel modified oligonucleotides. Novel modified siRNA are also provided.