Related Experiment Video

Updated: Sep 23, 2025

High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses
11:34

High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses

Published on: May 5, 2014

14.0K

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
PubMed

Insights

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.
Keywords:
autoregulatory circuitfeedbacknucleic acidssynthetic biologytranscriptional feedbackviral evolution

More Related Videos

Early Viral Entry Assays for the Identification and Evaluation of Antiviral Compounds09:29

Early Viral Entry Assays for the Identification and Evaluation of Antiviral Compounds

Published on: October 29, 2015

30.4K
High Throughput In Vitro Assessment of Latency Reversing Agents on HIV Transcription and Splicing07:18

High Throughput In Vitro Assessment of Latency Reversing Agents on HIV Transcription and Splicing

Published on: January 22, 2019

5.9K

Related Concept Videos

Viruses with RNA Genomes01:29

Viruses with RNA Genomes

RNA viruses are categorized into positive-strand, negative-strand, or double-stranded groups based on their genomic structure and replication mechanisms. This classification dictates how they exploit host cellular machinery for protein synthesis and replication. Some RNA viruses also utilize reverse transcription as part of their life cycle, further diversifying their replication strategies.Positive-Strand RNA VirusesPositive-strand RNA viruses have genomes that function directly as messenger...
169
Retrovirus Life Cycles01:10

Retrovirus Life Cycles

Retroviruses have a single-stranded RNA genome that undergoes a special form of replication. Once the retrovirus has entered the host cell, an enzyme called reverse transcriptase synthesizes double-stranded DNA from the retroviral RNA genome. This DNA copy of the genome is then integrated into the host’s genome inside the nucleus via an enzyme called integrase. Consequently, the retroviral genome is transcribed into RNA whenever the host’s genome is transcribed, allowing the...
47.1K
Size and Structure of Viral Genomes01:26

Size and Structure of Viral Genomes

Viral genomes exhibit remarkable diversity in size, structure, and composition, influencing their replication strategies and interactions with host cells. These genomes consist of either DNA or RNA and may be linear or circular. Additionally, they can be single-stranded or double-stranded, with each configuration affecting how the virus propagates within a host. RNA viruses, for instance, generally have smaller genomes than DNA viruses, a factor that contributes to their high mutation rates and...
180
Viral Mutations00:36

Viral Mutations

A mutation is a change in the sequence of bases of DNA or RNA in a genome. Some mutations occur during replication of the genome due to errors made by the polymerase enzymes that replicate DNA or RNA. Unlike DNA polymerase, RNA polymerase is prone to errors because it is not capable of “proofreading” its work. Viruses with RNA-based genomes, like HIV, therefore accrue mutations faster than viruses with DNA-based genomes. Because mutation and recombination provide the raw material...
33.6K
Subviral Agents01:29

Subviral Agents

Subviral agents are infectious entities that resemble viruses but lack one or more viral components, such as a capsid or essential replication machinery. These agents include viroids, prions, and satellites, each possessing distinct structural and functional characteristics that influence their mode of infection and replication.Viroids are the simplest subviral agents, consisting of circular, single-stranded RNA molecules without a protein coat. They exclusively infect plants, relying entirely...
144
Retroviruses02:33

Retroviruses

Retroviruses and retrotransposons both insert copies of their genetic elements into the genome of the host cell. Thus, the viral genes are passed on when the host genome is replicated or translated. A typical retroviral DNA sequence contains 3-4 genes that encode the different proteins required for its structural assembly and function as a molecular parasite. This DNA is transcribed into a single mRNA, which is very similar in structure to conventional mRNAs, i.e., it is capped at the 5’...
12.7K