Modified Oligonucleotide Phosphate Chemistry for Cell Uptake
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current oligonucleotide analogues face challenges in achieving efficient cell uptake and in vivo delivery without external delivery agents, exhibit acid sensitivity, and have difficulty in chemical modification for structure-activity studies, leading to high costs and reduced therapeutic efficacy.
Innovation Solution
Development of oligonucleotide analogues with modified phosphate groups, such as phosphoryl imines and analogues, that are charge neutral or positively charged, retain a conventional nucleotide backbone, display structural flexibility, and possess improved chemical stability, allowing for diverse side-chain modifications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If conventional phosphate groups are used in oligonucleotide analogues, then the synthesis is straightforward and costs are reduced, but cell uptake and in vivo delivery efficiency are poor
Solution Approach 1:
The patent modifies the phosphate group parameters by changing the charge state from negative to neutral or positive, and altering the chemical structure to phosphoryl imines and analogues. This transforms the physico-chemical properties to enhance cell membrane permeability and uptake efficiency while maintaining synthetic feasibility through established chemistry modifications.
2Productivity
If oligonucleotide analogues are designed to improve cell uptake, then therapeutic efficacy increases, but acid sensitivity and chemical stability deteriorate
Solution Approach 1:
The patent changes the chemical parameters of the phosphate group by introducing phosphoryl imine structures with modified bonding characteristics. This creates a more stable linkage that resists acid hydrolysis while maintaining the charge-neutral or positive characteristics needed for enhanced cell uptake and therapeutic activity.
3Productivity
If modified phosphate groups are introduced to enhance cell uptake, then therapeutic efficacy improves, but synthesis complexity and cost increase
Solution Approach 1:
The patent modifies existing phosphate groups through controlled chemical transformations rather than requiring entirely new synthetic pathways. The phosphoryl imine structures can be introduced using established phosphoramidite chemistry with modified reagents, maintaining compatibility with automated synthesizers and reducing overall synthesis complexity compared to completely novel structures.
Data Source
AI summary
Modified oligonucleotides that contain one or more of the phosphate groups substituted at phosphorus and methods for their synthesis are disclosed.