Antisense Morpholino Oligonucleotides Targeting Conserved Influenza RNA
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Solution Overview
Problem
Current treatments for influenza A virus infections are inadequate due to the virus's propensity for antigenic drift and shift, leading to unpredictable outbreaks and resistance to existing therapies, and vaccines fail to provide long-term protection against various strains.
Innovation Solution
Development of antisense oligonucleotides that target specific regions of the influenza virus RNA, such as the 5′ or 3′ terminal bases, AUG start codons, and splice sites, using morpholino subunits with phosphorodiamidate linkages and arginine-rich peptides to enhance uptake and efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If vaccines are used to prevent influenza, then protection rate is improved in healthy adults, but protection rate deteriorates in high-risk groups and against unexpected strains
Solution Approach 1:
The patent develops antisense oligonucleotides that target highly conserved regions of the influenza virus genome (such as the polymerase genes PB1, PB2, and PA), which are essential for viral replication across all influenza strains. This approach creates a universal antiviral mechanism that can protect against multiple strains and subtypes simultaneously, including unexpected variants, rather than strain-specific vaccines.
Solution Approach 2:
The invention employs antisense oligonucleotides that bind to and block essential viral genomic regions before the virus can complete its replication cycle. By targeting conserved sequences that are critical for viral function, the treatment prevents viral replication at an early stage, providing broad-spectrum protection against diverse influenza strains.
2Reliability
If current anti-influenza drugs are used, then some therapeutic effect is achieved, but capacity to provide protection deteriorates due to resistance and limited efficacy
Solution Approach 1:
The patent extracts and targets the essential, highly conserved genomic regions of the influenza virus (such as the polymerase genes) that are critical for viral replication. By focusing on these indispensable viral elements rather than surface proteins like hemagglutinin and neuraminidase, the antisense oligonucleotides achieve broad-spectrum antiviral activity that is less susceptible to resistance development.
Solution Approach 2:
The invention changes the molecular target parameter from surface glycoproteins (hemagglutinin and neuraminidase) to internal conserved genomic regions (polymerase genes PB1, PB2, and PA). This parameter change targets essential viral replication machinery that is more conserved across strains and less prone to mutation, thereby reducing resistance development while maintaining therapeutic efficacy.
3Reliability
If antisense oligonucleotides are designed to target viral RNA, then viral replication is inhibited, but delivery and uptake into host cells becomes challenging
Solution Approach 1:
The patent employs composite oligonucleotide structures combining antisense sequences with modified backbones (such as phosphorodiamidate morpholino oligomers or peptide nucleic acids) and conjugates them with cell-penetrating peptides or lipid formulations. This composite approach maintains the antisense mechanism's ability to inhibit viral replication while enhancing cellular uptake and delivery efficiency.
Solution Approach 2:
The invention uses cell-penetrating peptides, lipid carriers, or other delivery vehicles as intermediaries to facilitate the entry of antisense oligonucleotides into host cells. These intermediary carriers protect the oligonucleotides from degradation, enhance cellular uptake, and enable effective delivery of the antiviral agents to their target sites within infected cells.
Data Source
AI summary
The present invention relates to antisense antiviral compounds and methods of their use and production in inhibition of growth of viruses of the Orthomyxoviridae family and in the treatment of a viral infection. The compounds are particularly useful in the treatment of influenza virus infection in a mammal. Exemplary antisense antiviral compounds are substantially uncharged, or partially positively charged, morpholino oligonucleotides having 1) a nuclease resistant backbone, 2) 12-40 nucleotide bases, and 3) a targeting sequence of at least 12 bases in length that hybridizes to a target region selected from the following: a) the 5′ or 3′ terminal 25 bases of the negative sense viral RNA segment of Influenzavirus A, Influenzavirus B and Influenzavirus C; b) the terminal 30 bases of the 5′ or 3′ terminus of the positive sense vcRNA; c) the 45 bases surrounding the AUG start codon of an influenza viral mRNA and; d) 50 bases surrounding the splice donor or acceptor sites of influenza mRNAs subject to alternative splicing.