Broad-spectrum antiviral compounds that inhibits pyrimidine biosynthesis, triggers innate immunity, and induces antiviral responses.
Current therapeutics for viral diseases function by targeting viral gene products but are generally prone to developing resistant mutants and have a very narrow range of specificity. The rapid emergence of new viral strains as well as the continued geographic spread of diseases underscore the need to develop therapeutics that can more effectively target a broad range of viral pathogens. To date, the development of broad-spectrum antiviral agents has yielded therapeutics with limited efficacy and undesirable toxic side effects. Hence, there is significant emphasis on the development of new antiviral treatments to overcome current limitations as well as thwarting drug resistance.
This technology provides a novel, broad spectrum antiviral compounds with therapeutic applications for multiple strains of alphaviruses (Chikungunya) as well as members of other viral families including Orthomyxoviridae (including Influenza virus A, H1N1), Arenaviridae, Paramyxoviridae (RSV), Flaviviridaea, and Filoviridae (ebola).
The compounds have antiviral activity against a broad range of RNA viruses. This compound's ability to inhibit viral replication involves inhibiting pyrimidine synthesis, at least in part. Pyrimidines serve as the basic building blocks for multiple biochemical molecules, which are critical for cell growth and homeostasis. Studies have also revealed that the lead compound establishes an antiviral state by inducing a variety of interferons-stimulated genes (ISG). Notably, the compound functions independently of the production of type 1 interferons, demonstrating its unique mode of action for triggering innate immunity. Importantly, it is not toxic to cells at the effective concentration for inhibition of virus replication. Also of note, the antiviral activity of the lead compound is cell-type dependent with a robust effect in human cell lines and no effect in mouse cell lines.
-Broad spectrum activity for multiple viral strains belonging to alphavirus family.
-Broad spectrum activity for multiple pathogens from other virus families.
-No virus-specific therapeutics currently exist for Chikungunya, RSV, Ebola.
-Robust activity in human cell lines, not in mouse cell lines. High specificity.
-Not toxic to cells. IC50 values are in the nanomolar range.
-Novel mechanism of action that triggers innate immunity.
Currently there are no virus-specific therapeutics for Chikungunya, RSV, or Ebola. Additionally, this compound displays broad-spectrum activity for multiple pathogens from multiple viral families. This is in contrast to current therapeutics, which have a narrow range of activity.
This compound could be used to examine cellular mechanisms involved in pyrimidine synthesis, and further elucidate the role of interferons and associated genes in innate immunity.