Bimolecular Quadruplex-Duplex Hybrid Oligonucleotides for Gene Expression
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Solution Overview
Problem
Current methods for modulating gene expression through nucleic acid structures, such as antigene and antisense oligonucleotides, face limitations in targeting and stabilizing G-quadruplex structures, which are prevalent in genomic regions like oncogenic promoters, limiting their effectiveness in transcriptional regulation.
Innovation Solution
The development of an isolated oligonucleotide molecule that forms a bimolecular quadruplex-duplex hybrid with a target nucleic acid, using G-rich segments to complete a G-tetrad core, allowing for the induction of stable G-quadruplex structures in regions that otherwise cannot form them, thereby modulating gene expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antigene or antisense oligonucleotides are used to target G-rich sequences, then gene expression modulation is achieved, but the ability to stabilize G-quadruplex structures is insufficient
Solution Approach 1:
The patent applies composite materials by designing oligonucleotides that combine two distinct functional elements: a first element complementary to the target G-rich sequence and a second element capable of forming G-quadruplex structures. This composite oligonucleotide simultaneously achieves sequence-specific binding and stable quadruplex formation, resolving the contradiction between gene expression modulation effectiveness and G-quadruplex structure stability.
Solution Approach 2:
The invention merges two separate functions into a single oligonucleotide molecule: the antigene/antisense binding function and the G-quadruplex stabilization function. By combining these functions in one molecule, the patent achieves both effective gene expression modulation and stable G-quadruplex structure formation, directly addressing the technical contradiction.
2Stability of the object's composition
If modified nucleotides or intercalators are conjugated to enhance binding affinity, then binding stability improves, but the specific induction of G-quadruplex structures is limited
Solution Approach 1:
The patent applies local quality by designing the oligonucleotide with distinct functional regions: a first element for sequence-specific binding and a second element specifically engineered to form G-quadruplex structures. This localized functional differentiation allows the molecule to achieve both high binding stability and specific G-quadruplex induction capability, resolving the contradiction between binding stability and structural induction versatility.
3Productivity
If conventional oligonucleotides target mRNA for translational inhibition, then translational blockade is achieved, but transcriptional regulation through G-quadruplex stabilization is insufficient
Solution Approach 1:
The patent applies universality by designing an oligonucleotide that can function at multiple levels of gene expression control. The same oligonucleotide structure can target both DNA (for transcriptional regulation via G-quadruplex formation) and mRNA (for translational inhibition), making it a multi-functional agent that addresses both transcriptional and translational regulation needs, thereby resolving the contradiction between overall gene regulation efficacy and specific transcriptional regulation effectiveness.
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
This approach enables specific modulation of gene expression by stabilizing G-quadruplex structures, potentially down-regulating oncogenic promoters, and provides a direct route for transcriptional or translational blockade, enhancing the specificity and efficacy of gene regulation.
Implementation Method 1
a first nucleotide sequence substantially complementary to a segment of target nucleic acid molecule to allow hybridization of the oligonucleotide molecule to said target
Implementation Method 2
The G-quadruplex is a four-stranded helical assembly made up of multiple stacked G⋅G⋅G⋅G tetrads
Implementation Method 3
The resulting hybrid structure comprises a duplex element and a quadruplex element in coaxial alignment
Data Source
AI summary
A method for the generation of a G-quadruplex structure on a target nucleic acid sequence is presented. The approach combines the specificity of Watson-Crick base pair with the stability associated with a robust G-quadruplex scaffold. The induction of such bimolecular quadruplex-duplex hybrids can be applied within the antigene or antisense context for enhanced steric blockage to the transcriptional or translational machinery. In addition, such structures provide unique features for ligand design. This approach also allows the site-specific generation of G-quadruplex structures within nucleic acid nanoarchitectures.