5-Position Modified Pyrimidine Nucleosides for Aptamer Nuclease Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a need for alternative modified nucleosides and nucleotides that can be incorporated into oligonucleotides, such as aptamers, to enhance properties such as nuclease stability, net charge, hydrophilicity or lipophilicity, and target binding capabilities.
Innovation Solution
Development of 5-position modified pyrimidine nucleosides, including compounds with phenyl groups covalently attached through linkers, which can be incorporated into oligonucleotides and aptamers, enhancing their stability and binding affinity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If modified nucleosides are incorporated into oligonucleotides to improve nuclease stability, then stability is improved, but the complexity of the oligonucleotide structure increases
Solution Approach 1:
The patent applies parameter changes by systematically varying the chemical parameters of nucleoside modifications at the 5-position of pyrimidine bases. Different linker types (amides, esters, carbamates, sulfones, etc.) and aromatic moieties (phenyl, naphthyl, heteroaryl groups) are introduced to optimize nuclease stability while maintaining manageable structural complexity through controlled parameter variation rather than uncontrolled structural elaboration.
Solution Approach 2:
The patent employs composite materials by combining modified pyrimidine nucleosides with standard nucleotide components in oligonucleotide sequences. The composite structure integrates modified and unmodified nucleotides strategically to achieve enhanced nuclease stability in specific regions while preserving overall sequence functionality and manageable complexity through selective placement of modified components.
2Reliability
If modified nucleosides with aromatic groups are used to enhance target binding affinity, then binding affinity is improved, but the hydrophobicity of the oligonucleotide increases
Solution Approach 1:
The patent applies local quality by introducing aromatic moieties at specific positions within the oligonucleotide sequence rather than uniformly throughout. The modified pyrimidine nucleosides are placed at strategic locations where they can enhance target binding affinity through localized aromatic interactions while minimizing overall hydrophobicity by keeping the majority of the sequence composed of standard, more hydrophilic nucleotides.
Solution Approach 2:
The patent uses parameter changes by selecting aromatic groups with varying hydrophobicity characteristics and adjusting their placement based on the desired balance between binding affinity and solubility. Different aromatic moieties (phenyl, naphthyl, heteroaryl) with distinct hydrophobic parameters are chosen to optimize the trade-off between enhanced target binding and acceptable hydrophobicity levels.
3Adaptability or versatility
If multiple types of modified nucleosides are incorporated to alter net charge and hydrophilicity, then these properties are improved, but the difficulty of synthesis increases
Solution Approach 1:
The patent applies segmentation by dividing the oligonucleotide sequence into regions with different modification densities. Clusters of modified pyrimidine nucleosides are placed in specific segments where charge and hydrophilicity alterations are most beneficial, while other segments maintain standard nucleotide composition to simplify synthesis. This segmented approach allows property optimization without requiring uniform modification throughout the entire sequence, thereby reducing overall synthesis complexity.
Solution Approach 2:
The patent employs universality by designing modified pyrimidine nucleosides that can serve multiple functions simultaneously - providing nuclease stability, adjusting net charge, modifying hydrophilicity, and potentially enhancing binding affinity. This multi-functionality reduces the need for multiple different modification types, simplifying the synthesis process while achieving diverse property optimizations through a single versatile modification platform.
Data Source
AI summary
Compounds comprising 5-position modified pyrimidines are provided. Further, polynucleotides, such as aptamers, comprising at least one 5-position modified pyrimidine are provided. Methods of selecting and using such polynucleotides, such as aptamers, are also provided.