Modified Double-Stranded siRNA Conjugates for HBV Gene Silencing
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Solution Overview
Problem
Current hepatitis B treatment drugs, such as interferon and nucleoside analogs, face issues like drug resistance and adverse reactions, necessitating a more effective genetic silencing mechanism to inhibit HBV replication.
Innovation Solution
Development of a novel double-stranded siRNA with modified nucleotides and conjugates that enhance gene expression inhibition activity and reduce toxicity, utilizing RNA interference to silence HBV genes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If interferon or nucleoside analogs are used to treat hepatitis B, then viral replication can be inhibited, but drug resistance develops and adverse reactions occur
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of siRNA molecules through various nucleotide modifications (2'-O-methyl, phosphorothioate linkages, locked nucleic acids) to alter their physical and chemical properties, thereby improving stability and reducing immunogenicity while maintaining gene silencing effectiveness
Solution Approach 2:
The patent employs composite materials by creating conjugates that combine siRNA with carrier molecules such as galactosylated cholesterol, cell-penetrating peptides, and lipid nanoparticles, forming composite structures that enhance delivery efficiency, protect against degradation, and reduce toxic side effects
2Reliability
If siRNA is used to silence HBV genes, then viral replication is blocked at the genetic level, but delivery efficiency and stability are insufficient
Solution Approach 1:
The patent applies preliminary action by pre-modifying siRNA molecules with protective chemical groups and pre-conjugating them with delivery carriers before administration, ensuring they are stable and ready for effective delivery upon entering the target system
Solution Approach 2:
The patent uses intermediary molecules such as cell-penetrating peptides, lipid conjugates, and nanoparticle carriers that mediate the delivery of siRNA into hepatocytes, protecting the siRNA from degradation and facilitating its entry into target cells
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 novel siRNA demonstrates higher gene expression inhibition and lower toxicity, providing a more effective treatment for hepatitis B by blocking viral replication at the genetic level.
Implementation Method 1
Small interfering ribonucleic acid, i.e., small interfering RNA (siRNA) or short interfering RNA, can based on the RNA interference (RNAi) mechanism, inhibit or block the expression of any target gene of interest
Implementation Method 2
Double-stranded siRNA forms an RNA-induced silencing complex (RISC) with cell-derived related enzymes and proteins. During RNA interference, the sense strand in the double-stranded siRNA is excluded from the complex, and the antisense strand guides RISC to bind to the homologous site of the target mRNA
Implementation Method 3
The target mRNA is then degraded by RNase III in the complex, thereby shutting down the expression of the target gene
Data Source
Figure 1~2
AI summary
The present invention provides a novel double-stranded siRNA, conjugate thereof, and use thereof. The present invention provides a double-stranded siRNA, a conjugate thereof or a salt thereof, and also relates to use of the double-stranded siRNA and the conjugate thereof in preparing a medicament for treating and/or preventing hepatitis B. In addition, the present invention also relates to a novel compound, and a use of the compound in raw materials for solid-phase synthesis of DNA nucleotides, raw materials for synthesis of siRNA drugs, siRNA drug research, gene function research and/or screening of whole gene libraries, especially the use of the compound as a raw material for synthesis of the double-stranded siRNA drug described in the present invention. Furthermore, the present invention also relates to a novel nucleotide residue and its use in siRNA drug research, as a raw material for the synthesis of gene function research, and/or as a raw material for screening of whole gene libraries, as well as as an embedding group in oligonucleotides.