Bridged Oligonucleotide Chemistry for Reduced Off-Target Binding
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Solution Overview
Problem
Nucleic acid drugs face issues of non-specific binding due to the formation of non-Watson-Crick base pairs, leading to off-target effects and side effects, and have stability challenges as nuclease substrates.
Innovation Solution
A nucleic acid compound is developed with bridged 2'- and 4'-positions and modified 2-position carbonyl groups to suppress non-Watson-Crick base pair formation, enhancing affinity for complementary nucleic acids and reducing non-specific binding.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antisense oligonucleotides are used to treat genetic diseases, then gene expression can be inhibited, but the compounds have limited pharmacokinetic properties and poor tissue penetration
Solution Approach 1:
The patent applies composite materials by combining oligonucleotide chains with modified sugar moieties (e.g., cyclohexyl, adamantane, or indane rings) and lipid conjugates to create hybrid molecules. These composite structures integrate the sequence-specific binding capability of oligonucleotides with the membrane-permeating and pharmacokinetically favorable properties of lipid-modified cyclic compounds, thereby improving tissue penetration and pharmacokinetic profile while maintaining gene expression inhibition capability.
2Reliability
If conventional oligonucleotides are administered, then they can bind to target RNA, but they exhibit poor cell permeability and are rapidly cleared from circulation
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of oligonucleotides through conjugation with lipid-containing cyclic compounds. This structural modification alters key parameters including molecular size, hydrophobicity, and charge distribution, which collectively improve cell membrane permeability and extend circulation half-life by reducing renal clearance and protecting from nucleases, while preserving the ability to bind target RNA.
3Duration of action of stationary object
If oligonucleotides are modified to improve pharmacokinetics, then circulation time increases, but manufacturing complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the modified oligonucleotide structure into distinct functional modules: the oligonucleotide chain segment for target recognition, the cyclic linker segment (containing rigid rings like cyclohexane or adamantane), and the lipid segment for membrane interaction and pharmacokinetic optimization. This modular segmentation enables systematic synthesis and quality control, reducing manufacturing complexity compared to fully integrated modified structures.
Data Source
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Figure 3
AI summary
The present invention aims to provide a nucleic acid compound that hardly forms non-Watson-Crick base pairs, and an oligonucleotide containing the nucleic acid compound and showing reduced non-specific binding with nucleic acids other than the target nucleic acid. The nucleic acid compound according to the present invention is characterized in that the 2-position carbonyl group of the pyrimidine base is functionally converted (X1 and X2 are each independently S or Se), and that the 2'-position and the 4'-position are bridged in a particular structure. The oligonucleotide according to the present invention is characterized in that at least one of thymidine and uridine is the nucleic acid compound.