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-12195451-B2
Publication Date
2025-01-14
Expiration Date
2036-01-26
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Abstract
Provided are compounds of Formula III 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 relates to compounds, methods, and compositions that enhance viral infection, growth, spread, and/or productivity. Specifically, it provides compounds of formulae such as Formula III and others, which increase the spread of viruses in cells, increase viral titers in cells, and enhance antigen, gene, transgene, or viral protein expression. These compounds act as viral sensitizers, improving the efficiency of viruses, including attenuated and genetically modified viruses, in infecting and reproducing in a variety of cells.
The problem addressed is the innate cellular antiviral response which acts as a primary defense against viral replication and spread, limiting viral productivity. Attenuated viruses used in vaccines and therapies often have compromised growth in production cells due to antiviral responses. Existing compounds like VSe1 enhance viral productivity but suffer from instability and high electrophilicity, limiting their utility. Therefore, there is a need for compounds that enhance viral production with improved stability, reduced electrophilicity, and a favorable mutagenicity profile.
The invention provides novel compounds structurally related to VSe1 but with enhanced stability and viral sensitizing activity. These compounds include various chemical derivatives, such as those with different substitutions on heterocyclic rings and functional groups, which retain or improve the efficacy seen with VSe1. The invention also contemplates methods of using these compounds to increase viral infection, spread, titer, and production in diverse cell types and in ovo. Additionally, compositions, pharmaceutical carriers, and kits comprising these compounds with viruses and cells are disclosed to facilitate their application in vaccine and oncolytic virus production, gene therapy vector enhancement, and related fields.
Claims Coverage
The patent includes one independent claim focusing on a compound of Formula III, with several dependent claims elaborating on specific structural variations and compositions.
Compound of Formula III with specific substitutions
A compound defined by formula (III), or its pharmaceutically acceptable salts or stereochemically isomeric forms, wherein X5 is defined as hydrogen, substituted or unsubstituted linear or branched C1-C12 alkyl, alkenyl, alkynyl, mono- or bi-cycloaryl or -heteroaryl, cycloalkyl or heterocycloalkyl. Specific examples include alkynyloxy, phenyl, benzyl, triazolyl, naphthalenyl, pyridinyl, furanyl, thiophenyl, sulfonobenzyl, methylsulfonobenzyl, pyrrolyl, morpholine, cycloalkyl, alkylthiol, alkyamine, or oxazoline.
Substitution specificity of X5 for enhanced viral sensitizing compounds
X5 can be a linear or branched C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C5 cycloalkyl group, unsubstituted or substituted with phenyl, morpholinyl, naphthyl, pyridinyl, furyl, thienyl, triazolyl, oxazolyl, thiol, amino, or sulfonamide groups.
Compounds with X5 as substituted C1-C6 alkyl bearing specific phenyl substitutions
X5 is a linear or branched C1-C6 alkyl substituted with phenyl groups that are further substituted with methoxy, hydroxyl, phenyl, chlorine, fluorine, methyl sulfone, trifluoromethyl, or nitro groups.
Compounds with X5 as substituted C1-C6 alkyl with triazolyl substitution
X5 is a linear or branched C1-C6 alkyl substituted with one or more triazolyl groups, where the triazolyl may be further substituted with C1-C6 alkylene carboxyl esters or benzyl groups.
Specific compounds enumerated as viral sensitizing agents
The patent claims a group of specific compounds listed by name and structure as representative viral sensitizers.
Pharmaceutical compositions containing compounds of formula (III)
Compositions comprising at least one compound of formula (III) along with pharmaceutically acceptable carriers, diluents, or excipients for use in enhancing viral production.
The independent claim covers compounds of Formula III with specific substituents that enhance viral infection and production. Dependent claims specify chemical groups and substitutions, enumerated compound examples, and pharmaceutical compositions containing these compounds, collectively defining the scope of viral sensitizing agents and their applications.
Stated Advantages
The compounds enhance viral infection, growth, spread, and productivity in cells, including increasing viral titer and antigen expression.
Improved stability and reduced electrophilicity compared to prior compounds (e.g., VSe1) while retaining or enhancing viral sensitizing activity.
Some compounds demonstrate favorable mutagenicity profiles, being non-mutagenic in standard assays.
Compounds can synergistically enhance viral production when used in combination.
Effective in a variety of cell types including cancer, non-cancer, immortalized, primary cells, and embryonated eggs, facilitating broad applications.
Documented Applications
Enhancement of vaccine production including attenuated or genetically modified viruses in vitro or in ovo.
Increasing production of oncolytic viruses for cancer therapy.
Increasing yields of gene therapy vectors such as adenovirus and adeno-associated virus.
Enhancing production of viruses in embryonated chicken eggs, useful in vaccine manufacture.
Use in compositions and kits comprising viruses and susceptible cells or tissues to increase viral production.
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