A functional genomics-pharmacotranscriptomics framework identifies host-directed anti-influenza agents

Area of Science:

• Virology and Infectious Diseases
• Drug Discovery and Development
• Genomics and Bioinformatics

Background:

• Influenza A virus (IAV) poses a significant threat to public health globally.
• The emergence of drug-resistant IAV strains highlights the urgent need for novel antiviral therapies.
• Existing antiviral strategies face challenges due to rapid viral evolution and resistance development.

Purpose of the Study:

• To develop an integrative, host-directed drug discovery framework for identifying novel anti-IAV compounds.
• To leverage functional genomics and pharmacotranscriptomics for systematic antiviral screening.
• To discover drug candidates that modulate host gene expression towards an antiviral state, potentially reducing resistance.

Main Methods:

• Aggregated published genome-wide screens to assign functional scores to host genes based on their impact on IAV replication.
• Developed a pharmacotranscriptomic approach to screen nearly 20,000 drug-induced transcriptional signatures.
• Identified compounds capable of shifting host gene expression profiles towards an antiviral state.

Main Results:

• The framework successfully identified 54 potential anti-IAV compounds, with 18 demonstrating confirmed antiviral activity.
• Lithocholic acid and ALW-II-49-7 exhibited significant inhibition of IAV replication in vitro.
• These compounds provided protection against lethal IAV infection in vivo mouse models.

Conclusions:

• The developed host-targeted framework offers a systematic and scalable strategy for discovering novel antivirals.
• This approach yields antivirals less susceptible to resistance, addressing a critical limitation of current therapies.
• The methodology is potentially applicable to the discovery of treatments for other rapidly evolving pathogens.