Modified Oligonucleotides Enhancing Binding Affinity and Nuclease Resistance
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Solution Overview
Problem
Current oligonucleotides lack effective modifications to enhance their binding affinity, stability, and pharmacokinetic properties, particularly in diagnostics and therapeutic applications, where increased melting temperature, cell penetration, and resistance to nucleases are desired.
Innovation Solution
Development of modified nucleosides and oligonucleotides with specific chemical modifications, such as those described in formulas (2), (4), (6), (8), and (10), which include heterocyclic rings, alkyl groups, and phosphorus-containing internucleoside linkages, to improve binding, stability, and cellular uptake.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chemical modifications are introduced into oligonucleotides to increase binding affinity and stability, then the melting temperature and resistance to nucleases are improved, but the device complexity and manufacturing difficulty increase
Solution Approach 1:
The patent modifies the chemical parameters of oligonucleotides by introducing specific sugar modifications (2'-O-methyl, 2'-O-ethyl, 2'-O-propyl, 2'-O-isopropyl) and phosphorus-containing internucleoside linkages. These parameter changes in the molecular structure directly improve binding affinity, melting temperature, and nuclease resistance while maintaining a systematic approach to modification.
Solution Approach 2:
The invention creates composite oligonucleotide structures combining natural nucleosides with chemically modified nucleosides. The composite nature of these molecules integrates the binding properties of natural nucleic acids with the enhanced stability and resistance properties of chemically modified analogs, achieving multiple improvements simultaneously.
2Productivity
If chemical modifications are introduced to improve pharmacokinetic properties and cell penetration, then the therapeutic effectiveness is improved, but the manufacturing precision and ease of production deteriorate
Solution Approach 1:
The patent systematically varies the alkyl chain length and type (methyl, ethyl, propyl, isopropyl) at the 2'-O position of the sugar to optimize pharmacokinetic properties. This parameter variation approach allows tuning of cell penetration and therapeutic effectiveness while providing a clear manufacturing roadmap for producing different analogs.
3Reliability
If multiple chemical modifications are combined to achieve optimal performance, then the binding affinity and stability are maximized, but the device complexity and synthesis difficulty increase
Solution Approach 1:
The patent segments the oligonucleotide sequence into regions with different modification patterns. Not all nucleosides need to be modified, and when they are, different types of modifications can be applied to different positions. This segmentation allows optimization of binding and stability in critical regions while keeping the overall synthesis manageable by limiting modifications to specific segments.
Data Source
AI summary
The present invention provides nucleosides of formula (1) and oligonucleotides comprising at least on nucleoside of formula (2):Formula (1) and Formula (2). Another aspect of the invention relates to a method of inhibiting the expression of a gene in call, the method comprising (a) contacting an oligonucleotide of the invention with the cell; and (b) maintaining the cell from step (a) for a time sufficient to obtain degradation of the mRNA of the target gene.