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High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses
Published on: May 5, 2014
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Disrupting autorepression circuitry generates "open-loop lethality" to yield escape-resistant antiviral agents
Sonali Chaturvedi1, Michael Pablo1, Marie Wolf1
1Gladstone/UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
Cell
|May 13, 2022
Summary
Disrupting negative feedback in gene networks with nucleic-acid decoys causes viral "open-loop lethality," inhibiting replication. This novel antimicrobial strategy shows high resistance barriers against viruses like herpesviruses and SARS-CoV-2.
Area of Science:
- Molecular Biology
- Virology
- Genetics
Background:
- Gene-regulatory networks utilize autorepression (negative feedback) for homeostasis and to prevent aberrant gene expression.
- Viral replication relies on complex gene-regulatory networks that can be targeted for therapeutic intervention.
Purpose of the Study:
- To investigate if disrupting transcriptional negative feedback in viruses can inhibit replication and establish a high barrier to resistance.
- To demonstrate a novel therapeutic strategy termed "open-loop lethality" by breaking viral homeostasis.
Main Methods:
- Utilized nucleic-acid decoys mimicking cis-regulatory sites to disrupt negative feedback loops in viral gene expression.
- Assessed viral replication, cytotoxicity, synergy with existing antivirals, and resistance evolution in herpesviruses and SARS-CoV-2 models.
- Evaluated therapeutic efficacy in a mouse model of herpesvirus infection.
Main Results:
- Feedback disruptors reduced herpesvirus replication by over 2 logs, with sub-nanomolar IC50 values, without activating innate immunity.
- This approach synergized with standard antivirals and showed efficacy in vivo, with no resistance mutants emerging in long-term cultures.
- Disruption of a SARS-CoV-2 feedback circuit also induced open-loop lethality, reducing viral titers by over 1 log.
Conclusions:
- Disrupting negative feedback to generate "open-loop lethality" is a viable strategy for antiviral therapy.
- This approach offers a high genetic barrier to resistance, contrasting with current antiviral limitations.
- Nucleic-acid decoys represent a promising new class of antimicrobials targeting viral gene regulation.
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