Artificial Nucleic Acid Structure Induction for Mutation-Tolerant Binding
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Solution Overview
Problem
Existing nucleic acid therapeutics face instability due to mutations in target sequences, leading to attenuated binding, and there is a lack of methods to form stable non-complementary base pairs for functional three-dimensional structures.
Innovation Solution
Development of an artificial nucleic acid that hybridizes with a target nucleic acid to induce a specific three-dimensional structure, incorporating complementary and non-complementary sequences, and can include modified nucleotides to enhance stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If conventional nucleic acid therapeutics (ASO/siRNA) are used, then they are easy to design and apply, but drug efficacy becomes unstable when mutations occur in target sequences
Solution Approach 1:
The patent changes the binding mode parameter from conventional Watson-Crick base pairing to non-complementary base pairing (e.g., G-A sheared pairs, G-U wobble pairs). This parameter change allows the nucleic acid to maintain stable binding even when mutations occur in the target sequence, as the non-complementary pairing creates a more tolerant binding interface that can accommodate sequence variations while maintaining structural stability.
Solution Approach 2:
The patent employs composite nucleic acid structures that combine regions of complementary base pairing with regions of non-complementary base pairing. This composite approach allows the molecule to leverage both the specificity of complementary pairing and the mutation-tolerance of non-complementary pairing, creating a hybrid binding mechanism that maintains efficacy across diverse target sequences including those with mutations.
2Reliability
If non-complementary base pairs are used to achieve stable binding, then binding stability improves, but the method and basic knowledge for forming functional three-dimensional structures are lacking
Solution Approach 1:
The patent incorporates pre-designed non-complementary base pair motifs (such as G-A sheared pairs, G-U wobble pairs, and other non-Watson-Crick pairs) into the nucleic acid structure beforehand. These pre-formed structural elements naturally promote the formation of functional three-dimensional structures without requiring complex external assembly methods or additional processing steps, thereby reducing overall method complexity while maintaining binding stability.
Solution Approach 2:
The nucleic acid molecules are designed to self-assemble into functional three-dimensional structures through intrinsic non-complementary base pairing interactions. The molecules autonomously form stable complexes with target sequences without requiring external enzymes, proteins, or complex processing methods, allowing the system to serve itself in forming the necessary structural motifs for stable and specific binding.
3Adaptability or versatility
If mutations occur in target sequences, then genetic diversity is achieved, but binding between targets and nucleic acid therapeutics is attenuated
Solution Approach 1:
The patent fundamentally changes the base pairing parameter from strict complementary pairing to non-complementary pairing modes. This parameter change enables the nucleic acid therapeutic to bind to target sequences with mutations by utilizing alternative pairing geometries (such as sheared pairs, wobble pairs, and other non-Watson-Crick interactions) that are more tolerant of sequence variations, thereby maintaining binding strength across genetically diverse targets.
Solution Approach 2:
The nucleic acid molecules are designed with universal binding capabilities that can accommodate multiple target sequences including those with mutations. By incorporating non-complementary base pairing motifs that can interact with various nucleotide configurations, the therapeutic achieves multi-functionality in recognizing and binding to diverse target sequences, making it effective across different genetic variants and mutations.
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 artificial nucleic acid forms stable three-dimensional structures despite mutations, enabling effective gene expression inhibition and nucleic acid detection.
Implementation Method 1
nucleic acid molecules, such as DNA and RNA, are composed of nucleotides having 4 types of bases: adenine (A), thymine (T) (uracil (U) for RNA), guanine (G), and cytosine (C), in which A and T or U, and C and G tend to be base-paired, and this nature is called complementarity of base pairs
Implementation Method 2
it has been revealed that nucleic acids stably form non-complementary base pairs in vivo. For Example, Non-Patent Literature 1 discloses that in single-stranded nucleic acids that form functional three-dimensional structures, about 150 types of non-complementary base pairs form stable three-dimensional structures
Data Source
AI summary
A method for actively forming a three-dimensional structure, a modification mode for a nucleic acid maintaining a three-dimensional structure; and an artificial nucleic acid capable of stably binding to a target sequence regardless of mutation, by utilizing non-complementary base pairs in nucleic acid therapeutics are provided. An artificial nucleic acid for inducing a specific three-dimensional structure by hybridizing with a nucleic acid of interest that does not form a functional three-dimensional structure, a gene expression inhibiting agent and a nucleic acid detecting agent including the artificial nucleic acid as an active ingredient; and a method for producing an artificial nucleic acid are also disclosed.