Gapmer Antisense Oligonucleotides Degrade SARS-CoV-2 RNA
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Solution Overview
Problem
Current antisense oligonucleotide therapies have not been effective in treating SARS-CoV-2 infections due to limitations in chemistry and design, particularly with morpholino-based antisense oligomers that rely on steric blocking rather than RNA degradation.
Innovation Solution
Development of gapmer antisense oligonucleotides (AOs) using locked nucleic acids (LNA), 2′-O-methyl (2′-O-Me), and 2′-O-methoxyethyl (2′-MOE) modifications that target SARS-CoV-2 RNA for efficient degradation, combining in silico and bioinformatic analysis with in vitro testing to enhance potency, safety, and reduce toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If morpholino-based antisense oligomers are used, then steric blocking mechanism is achieved, but RNA degradation is not accomplished
Solution Approach 1:
The patent changes the chemical parameters of the antisense oligonucleotide by incorporating a gapmer structure with DNA gap region flanked by LNA or 2′-O-Me/2′-MOE wings. This parameter change enables RNase H recruitment and catalytic RNA degradation, transforming the mechanism from steric blocking to enzymatic degradation, thereby resolving the limitation of morpholino-based approaches.
Solution Approach 2:
The gapmer antisense oligonucleotide employs a composite structure combining different nucleic acid components: a central DNA gap region capable of recruiting RNase H, flanked by modified nucleotide wings (LNA or 2′-O-Me/2′-MOE) that provide enhanced binding affinity and stability. This composite design integrates the advantages of different material properties to achieve both stable target binding and catalytic RNA degradation.
2Productivity
If conventional antisense oligonucleotides are used, then RNA binding is achieved, but degradation efficiency is insufficient
Solution Approach 1:
The patent introduces RNase H as an intermediary enzyme that mediates RNA degradation. The gapmer antisense oligonucleotide serves as a substrate that recruits RNase H to the target RNA, enabling catalytic degradation. This intermediary mechanism significantly enhances degradation efficiency compared to direct steric blocking, as RNase H can process multiple RNA targets sequentially.
3Reliability
If increased oligonucleotide potency is achieved through chemical modifications, then RNA binding affinity improves, but toxicity may increase
Solution Approach 1:
The gapmer structure applies local quality modifications by placing chemically modified nucleotides (LNA or 2′-O-Me/2′-MOE) specifically in the wing regions flanking the central DNA gap. These local modifications enhance binding affinity and stability where needed, while the central DNA gap maintains compatibility with RNase H recruitment. This localized modification strategy achieves high potency while minimizing off-target effects and toxicity associated with extensive chemical modifications throughout the entire oligonucleotide sequence.
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 gapmer AOs effectively degrade SARS-CoV-2 RNA, providing a promising antisense therapy for COVID-19 treatment by targeting specific regions of the virus, including structural proteins and regulatory sequences, with demonstrated efficacy in reducing viral RNA levels in cell cultures.
Implementation Method 1
gapmer AOs that can effectively target SARS-CoV-2 RNA and efficiently degrade its RNA
Implementation Method 2
efficiently degrade its RNA using a combination of in silico and bioinformatic analysis and in vitro testing
Data Source
AI summary
SARS-CoV-2 causes pandemic COVID19. Developing an effective treatment to directly target the virus could significantly impact viral burden in those most vulnerable to the devastating effects of this virus. The invention provides antisense oligonucleotides (AOs) to target the single stranded RNA genome of the SARS-CoV-2 viruses. The administration of AOs can significantly reduce the target viral RNAs.