Compositions and methods for viral sensitization
Inventors
Diallo, Jean-Simon • Boddy, Christopher Noyce • Dornan, Mark • Krishnan, Ramya • ARULANANDAM, Rozanne • Le Boeuf, Fabrice • Smith, Jeffrey • Macklin, Andrew
Assignees
University of Ottawa • Ottawa Health Research Institute
Publication Number
US-11339146-B2
Publication Date
2022-05-24
Expiration Date
2036-01-26
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Abstract
Provided are compounds of Formula (II) that enhance the efficacy of viruses by increasing spread of the virus in cells, increasing the titer of virus in cells, or increasing the antigen expression from a virus, gene or trans-gene expression from a virus, or virus protein expression in cells. Other uses, compositions and methods of using same are also provided.
Core Innovation
The invention concerns compounds, methods, and compositions that enhance viral infection, growth, spread, and productivity. Specifically, the invention provides compounds of Formula (II) and related compounds that increase the spread of viruses in cells, increase viral titers, and enhance antigen, gene, trans-gene, or protein expression from viruses within cells. These viral sensitizing compounds function by impeding cellular antiviral responses, such as interferon signaling, thereby improving viral productivity in various cell types.
The problem addressed is the limitation in viral productivity due to innate cellular antiviral responses which restrict viral replication and spread. While attenuated viruses used in vaccines and therapeutics are safer, their growth is often compromised in cells used for production, such as normal, immortalized, cancer cells, or embryonated eggs. Existing compounds like Viral Sensitizer 1 (VSe1) can enhance viral productivity but have drawbacks such as high electrophilicity and low aqueous stability, which limit their practical use.
The invention solves this by identifying novel viral sensitizing compounds with reduced electrophilicity, improved stability, and favorable mutagenicity profiles. These compounds effectively enhance infection, spread, titer, antigen expression, and protein expression of a wide range of viruses, including oncolytic viruses, vaccines, and gene therapy vectors, across various cell types and embryonated eggs. The invention also includes synergistic combinations of compounds for improved viral sensitization.
Claims Coverage
The patent claims cover a method using compounds defined by Formula (V) with multiple inventive features related to enhancing viral production in cells.
Use of compounds of Formula (V) to enhance viral production in cells
A method comprising administering a compound of Formula (V) to cells to enhance or increase viral production.
Specific substitution on compound Formula (V)
The compound of Formula (V) wherein X7 is substituted or unsubstituted alkylamine, C1-C12 alkyl, substituted benzyl, unsubstituted phenyl, substituted phenyl, or substituted cycloalkyl.
Application to various cell types
The method applies to cultured cells, adherent or suspension cells, cancer or tumor cells, immortalized cells, primary or non-immortalized cells, normal cells, eggs, or egg cells derived from embryonated eggs.
Enhancement of viral production parameters
Enhancing or increasing viral production includes enhancing infection of cells and/or rate thereof, viral reproductive capacity, spread or titer and/or rate of titer development, antigen expression, gene or transgene expression, virus protein expression, or any combination thereof.
These inventive features collectively define a method of enhancing or increasing viral production through administering specifically substituted compounds of Formula (V) to various cell types, improving multiple aspects of viral infection and production.
Stated Advantages
Enhancement of viral infection, spread, and titer in cells and eggs.
Increased production of attenuated viruses, genetically modified viruses, vaccines, and gene therapy vectors.
Improved compound stability and reduced electrophilicity compared to prior art compounds.
Ability to synergistically combine compounds for greater viral sensitizing effects.
Non-mutagenic profiles in tested analogues enhancing safety.
Documented Applications
Increasing productivity of oncolytic viruses, such as VSVΔ51 and Maraba MG-1, in cancer cells.
Enhancing replication and spread of Herpes Simplex Virus Type-1 (HSV-1) in cancer cells.
Increasing output of influenza A virus strains in non-cancerous cells, including MDCK and Vero cells.
Enhancing gene therapy vector transduction, such as adenovirus and adeno-associated virus vectors in human lung carcinoma cells.
Improving viral production in embryonated chicken eggs (in ovo), demonstrated with influenza A/FM1 (H1N1) virus.
Use in preparation and production of vaccines containing attenuated or genetically modified viruses produced from cells.
Application in compositions and kits comprising viral sensitizing compounds, viruses, cells, media, and tools for culturing and infecting cells or eggs.
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