Segmented Oligonucleotides for Adenosine Editing in Complex Structures
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Solution Overview
Problem
Existing oligonucleotides for target adenosine editing often require sequences that are complementary to a consecutive range of nucleobases near the target adenosine, which can disrupt functional elements and are inefficient in complex structures, and rely on exogenous proteins for editing.
Innovation Solution
Design of oligonucleotides with multiple domains, each complementary to separate portions of the target nucleic acid, allowing for editing without consecutive sequence complementarity and utilizing endogenous ADAR proteins for efficient adenosine modification.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If an oligonucleotide is designed with a base sequence complementary to a consecutive range of nucleobases near the target adenosine, then the oligonucleotide can achieve adenosine editing, but it disrupts functional elements and shows reduced efficiency in complex structures
Solution Approach 1:
The oligonucleotide is divided into multiple domains (first domain, second domain, etc.), where each domain is complementary to a separate portion of the target nucleic acid. The portions are separated by gaps, allowing the oligonucleotide to bind to multiple discrete locations without requiring continuous complementarity, thereby avoiding disruption of functional elements while maintaining editing capability
Solution Approach 2:
Each domain of the oligonucleotide is designed with specific local complementarity to particular portions of the target nucleic acid. The gaps between domains allow for local variations in sequence composition, enabling the oligonucleotide to adapt to different structural contexts without imposing rigid consecutive complementarity that would disrupt functional elements
2Stability of the object's composition
If an oligonucleotide uses a longer consecutive sequence complementarity to ensure binding, then binding stability is improved, but it increases the risk of disrupting functional elements and reduces flexibility in complex structures
Solution Approach 1:
The binding interface is segmented into multiple discrete domains separated by gaps. Each domain provides localized binding stability through complementarity to specific portions, while the gaps provide flexibility and adaptability to complex structural contexts, allowing the oligonucleotide to accommodate variations in target structure without requiring long continuous complementary sequences
3Adaptability or versatility
If an oligonucleotide is designed to target adenosines in complex secondary structures, then editing capability is expanded, but conventional consecutive sequence designs show reduced efficiency
Solution Approach 1:
The oligonucleotide employs multiple domains separated by gaps, each targeting different portions of the target nucleic acid. This segmented design allows the oligonucleotide to access and bind to adenosines within complex secondary structures more effectively than conventional consecutive sequence designs, as the gaps permit the oligonucleotide to navigate and adapt to the three-dimensional folding and structural complexity of the target
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 designed oligonucleotides provide improved stability, selectivity, and efficiency in editing adenosines, especially in complex structures, while minimizing disruption and reducing immune response.
Implementation Method 1
the base sequence of the first domain is complementary to a first portion of the base sequence of a target nucleic acid; the base sequence of the second domain is complementary to a second portion of the base sequence of a target nucleic acid
Data Source
AI summary
Among other things, the present disclosure provides oligonucleotides, compositions and methods thereof that are useful for adenosine modification. In some embodiments, the present disclosure provides methods for treating various conditions, disorders or diseases that can benefit from adenosine modification.