Double-stranded oligonucleotide, composition and conjugate comprising double-stranded oligonucleotide, preparation method thereof and use thereof
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Solution Overview
Problem
Existing delivery systems for small RNA drugs, particularly for targeting liver cells, face challenges in stability and efficiency, leading to suboptimal therapeutic outcomes.
Innovation Solution
A double-stranded oligonucleotide comprising modified nucleotides, specifically with fluoro-modified nucleotides at strategic positions, designed to target and inhibit gene expression in hepatocytes, combined with a pharmaceutical composition and conjugate for enhanced delivery and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional double-stranded oligonucleotides are used for liver cell-targeted delivery, then delivery capability is achieved, but stability in blood and liver tissues is insufficient
Solution Approach 1:
The patent applies parameter changes by introducing fluoro modifications at specific positions (7, 8, 9 in sense strand; 2, 6, 14, 16 in antisense strand) and phosphorothioate linkages to alter the chemical properties of the oligonucleotide. These modifications change the nucleotide parameters to enhance resistance to nucleases and improve stability in blood and liver tissues, directly resolving the stability issue while maintaining delivery capability
Solution Approach 2:
The patent creates a composite structure by combining fluoro-modified nucleotides, phosphorothioate linkages, and targeting ligands into a single oligonucleotide conjugate. This composite material integrates multiple functional elements: the fluoro modifications provide stability, the phosphorothioate linkages enhance structural integrity, and the targeting ligands ensure liver-specific delivery, collectively solving both stability and delivery requirements
2Adaptability or versatility
If targeting ligands are conjugated to the oligonucleotide for liver-specific delivery, then targeting capability is improved, but structural complexity increases
Solution Approach 1:
The patent applies local quality by placing targeting ligands at specific locations on the oligonucleotide structure and concentrating fluoro modifications at particular positions (7, 8, 9 in sense strand; 2, 6, 14, 16 in antisense strand). This localized approach ensures that each region serves its specific function: the ligands provide targeting capability while the fluoro-modified regions provide stability, achieving adaptability without unnecessary structural complexity
3Reliability
If multiple fluoro modifications are introduced to enhance stability, then resistance to degradation is improved, but manufacturing complexity increases
Solution Approach 1:
The patent applies preliminary action by incorporating fluoro modifications and phosphorothioate linkages during the synthesis process rather than attempting to modify the oligonucleotide after synthesis. This preliminary incorporation of stability-enhancing features into the synthesis process simplifies manufacturing by avoiding complex post-synthesis modification steps, while still achieving the desired resistance to nuclease degradation
Data Source
AI summary
Provided is a modified double-stranded oligonucleotide, in which the sense strand comprises a nucleotide sequence 1, the anti-sense strand comprises a nucleotide sequence 2, the nucleotide sequences 1 and 2 are both 19 nucleotides in length, and in the direction from 5′ end to 3′ end, nucleotides at positions 7, 8 and 9 of the nucleotide sequence 1 and nucleotides at positions 2, 6, 14 and 16 of the nucleotide sequence 2 are all fluoro-modified nucleotides, and each nucleotide at other positions is independently one of non-fluoro-modified nucleotides. Further provided are a pharmaceutical composition and a conjugate comprising the oligonucleotide, and pharmaceutical use thereof.