G-Quadruplex Oligonucleotides With Phosphorothioate Stability
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Solution Overview
Problem
Current treatments for viral and bacterial infections, particularly those caused by emerging pathogens like SARS-CoV2, are limited by the efficacy of small molecule inhibitors and the need for effective drugs or vaccines, and existing oligonucleotide therapies face challenges in stability and target specificity.
Innovation Solution
Development of oligonucleotide molecules with a high guanosine or deoxyguanosine content that form G-quartets, which inhibit viral or bacterial replication and exhibit anti-inflammatory effects, utilizing phosphorothioate modifications for enhanced stability and target binding.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If small molecule inhibitors are used to treat viral and bacterial infections, then they are easily identified from compound libraries, but their action is confined to a small surface area of the target and single amino acid changes can significantly reduce efficacy
Solution Approach 1:
The patent replaces small molecule inhibitors with oligonucleotide molecules (aptamers) that bind to viral and bacterial targets through nucleic acid-base interactions rather than protein-protein interactions. This substitution provides several advantages: oligonucleotides have larger binding surfaces, can accommodate target mutations better, and offer improved stability. The aptamers are isolated using SELEX methodology, maintaining ease of identification while resolving the efficacy stability issue.
2Reliability
If existing oligonucleotide therapies are used, then they can bind to specific target molecules with high affinity, but they face challenges in stability and target specificity
Solution Approach 1:
The patent applies chemical modifications to the oligonucleotide backbone, specifically phosphorothioate modifications where non-bridging oxygen atoms are replaced with sulfur atoms. This parameter change in the molecular structure significantly enhances stability by protecting against nuclease degradation while maintaining high target binding affinity. The modified backbone preserves the ability to form G-quadruplex structures necessary for specific target recognition.
3Stability of the object's composition
If oligonucleotide molecules with high guanosine content are used to form G-quartets, then they show improved stability and target specificity, but the complexity of the molecular structure increases
Solution Approach 1:
The patent utilizes the dynamic folding properties of G-rich oligonucleotides that spontaneously form G-quadruplex structures under physiological conditions. The molecules contain 6-8 consecutive guanosine residues that dynamically fold into stable G-quartet arrangements with characteristic square planar geometries. This dynamic self-assembly provides structural stability without requiring complex external stabilization mechanisms, as the G-quadruplex structure forms autonomously through hydrogen bonding and cation coordination.
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 oligonucleotide molecules demonstrate strong antiviral and antibacterial activity, with improved stability and target specificity, effectively inhibiting replication and reducing inflammation, while minimizing immunogenicity and hydrolysis.
Implementation Method 1
G-quadruplexes are formed by the stacking of two or more G-quartets on top of each other
Implementation Method 2
four G-bases which are associated via Hoogsteen H-bonding to form a square planar structure
Implementation Method 3
utilizing phosphorothioate modifications for enhanced stability and target binding
Implementation Method 4
Oligonucleotide molecules which bind to specific target molecules ('aptamers') may be isolated using Systematic Evolution of Ligands by EXponential enrichment (SELEX) and may serve as affinity probes or molecular recognition elements
Data Source
AI summary
An oligonucleotide molecule has 10 to 50 nucleotides that include at least one G-quartet forming motif having 10 to 20 nucleotide residues. At least 60% of the residues of the G-quartet forming motif are guanosine or deoxyguanosine residues. The oligonucleotide molecule inhibits tumor growth and/or viral or bacterial replication and/or exerts anti-inflammatory effects in mammalian cells.