PB2 PSL2 RNA Targeting for Pan-Genotypic Influenza Inhibition
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Solution Overview
Problem
Current antiviral drugs for influenza A virus (IAV) are subtype limited and face rising resistance issues, necessitating a pan-genotypic approach to target a conserved RNA structural element across all subtypes.
Innovation Solution
Development of compositions that disrupt the Packaging Stem-Loop 2 (PSL2) structure in the 5' packaging signal region of genome segment PB2, using agents that specifically bind to the PSL2 motif to inhibit IAV, including oligonucleotides and antibodies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current antiviral drugs target specific viral proteins, then they can inhibit influenza virus, but they are subtype limited and face rising antiviral resistance
Solution Approach 1:
The patent applies universality by designing oligonucleotide compounds that target a conserved RNA structural element (PSL2) present across all influenza A virus subtypes. Instead of targeting subtype-specific viral proteins, the invention targets a universal packaging signal structure that is essential for viral RNA packaging in all IAV subtypes, thereby achieving broad-spectrum antiviral activity against diverse influenza strains including H1N1, H3N2, and avian subtypes
Solution Approach 2:
The patent employs parameter changes by shifting the target from protein-based (subject to mutation and resistance) to structured RNA-based (高度 conserved). The PSL2 RNA structure contains critical base-pairing interactions and tertiary structures that are evolutionarily constrained, making them less prone to mutation. This parameter shift from protein sequence to RNA structural motif enables sustained antiviral efficacy against evolving viral strains
2Manufacturing precision
If antiviral drugs are designed for specific subtypes, then they can be optimized for that subtype, but they cannot effectively inhibit other influenza A subtypes
Solution Approach 1:
The patent applies local quality by focusing on a specific local structural feature (PSL2 packaging stem-loop) within the viral genome that is locally conserved across all subtypes. While the overall viral genome and protein sequences vary between subtypes, this local RNA structural element maintains its critical packaging function and structural characteristics across all influenza A subtypes, making it an ideal target for pan-genotypic inhibition
3Adaptability or versatility
If oligonucleotide compounds target conserved RNA structural elements, then they achieve broad-spectrum activity, but the mechanism must disrupt essential viral packaging functions
Solution Approach 1:
The patent applies the taking out principle by extracting and isolating the PSL2 packaging signal structure from the complex viral genome for targeted inhibition. By designing oligonucleotide compounds that specifically bind to this extracted packaging signal, the invention disrupts the packaging function without affecting other viral proteins or genome segments, achieving selective inhibition of viral assembly while preserving host cell function
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
Achieves broad-spectrum inhibition of IAV across various subtypes, reducing viral titers by 1 log10 or more, and provides effective treatment and prevention strategies.
Implementation Method 1
compounds comprising an oligonucleotide sequence complementary to a PB2 motif of the vRNA
Data Source
AI summary
Methods of inhibiting influenza A virus in a sample are provided. Aspects of the methods include contacting a sample comprising viral RNA (vRNA) having a PSL2 motif with an effective amount of an agent that specifically binds the PSL2 motif to inhibit the influenza A virus. Also provided are methods of treating or preventing influenza A virus infection in a subject. Also provided are methods for screening a candidate agent for the ability to inhibit influenza A virus in a cell, the method comprising: contacting a sample with a candidate agent; and determining whether the candidate agent specifically binds to the PSL2 motif of vRNA. Also provided are compounds and pharmaceutical compositions comprising an oligonucleotide sequence complementary to a PB2 vRNA region that find use in the subject methods.