Pan-genotypic agents against influenza virus and methods of using the same
Inventors
Glenn, Jeffrey S. • Saluti, Rachel Hagey • Pham, Edward A.
Assignees
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Publication Number
US-12618063-B2
Publication Date
2026-05-05
Expiration Date
Abstract
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.
Core Innovation
The disclosure identifies Influenza A virus (IAV) PB2 Packaging Stem-Loop 2 (PSL2) as a conserved RNA structural element in the 5′ PB2 packaging signal region and as a pan-genotypic antiviral target in IAV. The approach centers on disrupting PSL2 structure to inhibit viral genome packaging.
Methods of inhibiting IAV are provided by contacting viral RNA, including isolated vRNA, virion-associated vRNA, or vRNA in infected cells, with an agent that specifically binds a PSL2 motif. The specific binding disrupts PSL2 structure and inhibits genome packaging, and the disclosure optionally includes recruiting RNase in connection with PSL2 binding.
The disclosure further provides treating or preventing methods in a subject and cell-based screening methods based on specific binding to PSL2. It also describes antiviral oligonucleotide options, including oligonucleotide sequences complementary to PB2 vRNA nucleotides 34–87 and defined oligonucleotide chemistries and modified nucleotides, including the oligonucleotide sequence 5′ CGACCAAAAGAATTC 3′ (SEQ ID NO:56) and an LNA14-form oligonucleotide noted as SEQ ID NO:81.
Claims Coverage
The partial content includes two independent claims, each directed to an antiviral oligonucleotide pharmaceutical composition with a specified oligonucleotide sequence. Dependent claims further refine inventive features such as internucleoside linkage chemistry, chiral internucleoside linkages, a length/functional constraint related to RNase recruitment, use for treating or preventing influenza A virus infection with at least about one week protection, and optional combination with additional active agents.
Antiviral oligonucleotide composition with SEQ ID NO:56 sequence
An antiviral oligonucleotide compound or salt thereof, comprising an oligonucleotide sequence 5′ CGACCAAAAGAATTC 3′ (SEQ ID NO:56).
Antiviral LNA14/DNA oligonucleotide composition with SEQ ID NO:81 sequence notation
An antiviral oligonucleotide compound or salt thereof, comprising an oligonucleotide sequence LNA14: 5′CGACcaaaagaATTC 3′ (SEQ ID NO:81), wherein capitalized letters denote LNA nucleotides and lowercase letters denote DNA nucleotides.
Across the independent claim coverage shown, the core inventive coverage is defined by pharmaceutical compositions comprising antiviral oligonucleotides that are constrained to specific sequence definitions. The disclosed dependent claim refinements further constrain oligonucleotide chemistry and structure, and include a functional length/RNase recruitment capability, with use directed to treating or preventing influenza A infection for at least about one week and optionally combining with an additional active agent.
Stated Advantages
Provides antiviral inhibition by disrupting PSL2 structure and inhibiting viral genome packaging.
Includes optional RNase recruitment in connection with PSL2 targeting.
Describes a resistance barrier higher than oseltamivir in drug-pressure passaging.
Documented Applications
Treating and/or preventing influenza A virus infection in a subject at risk, including protection for at least about one week.
Cell-based screening based on specific binding to the PSL2 motif.
Combination treatment/prevention in which a pharmaceutical composition further comprises either a second oligonucleotide active agent or an antiviral drug.
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