Evidence map›Paper›PMID 35561685›Full record

ArticleCell2022

Disrupting autorepression circuitry generates "open-loop lethality" to yield escape-resistant antiviral agents.

Sonali Chaturvedi, Michael Pablo, Marie Wolf, Daniel Rosas-Rivera, Giuliana Calia, Arjun J Kumar, Noam Vardi, Kelvin Du, Joshua Glazier, Ruian Ke and 3 more

Erratum issuedOpen access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
1.8field-weighted citation impact, top 14% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed, 11 citations in OpenAlex.

  1. Systems Virology at Scale.Current opinion in systems biology · 2025
    Article
  2. Review
  3. Adaptive DNA amplification of synthetic gene circuit opens a way to overcome cancer chemoresistance.Proceedings of the National Academy of Sciences of the United States of America · 2023
    Article
  4. Article
  5. Article
  6. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

13 authors at 3 institutions in 1 country.

Sonali ChaturvediGladstone/UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA. Electronic address: sonali.chaturvedi@gladstone.ucsf.edu.
Michael PabloGladstone/UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
Marie WolfGladstone/UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
Daniel Rosas-RiveraGladstone/UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
Giuliana CaliaGladstone/UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
Arjun J KumarGladstone/UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
Noam VardiGladstone/UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
Kelvin DuGladstone/UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
Joshua GlazierGladstone/UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
Ruian KeTheoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
Matilda F ChanFrancis I. Proctor Foundation, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94158, USA.
Alan S PerelsonTheoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
Leor S WeinbergerGladstone/UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: leor.weinberger@gladstone.ucsf.edu.
Gladstone Institutes · USLos Alamos National Laboratory · USUniversity of California, San Francisco · US

Funding

Virology CoreP30AI027763 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI STEVEN Grant DEEKS · 1988 to 2026
$93.6M
UC San Diego Clinical and Translational Research InstituteUL1TR001442 · NCATS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI FIRESTEIN, GARY S, HOGARTH, MICHAEL · 2015 to 2024
$88.3M
VirologyP30AI036214 · NIAID · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI SUSAN JANET LITTLE · 1994 to 2026
$78.4M
Rapid-Prototyping and Design CoreP30EY002162 · NEI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI ULLIAN, ERIK M · 1985 to 2024
$16.8M
Modeling Viral and T Lymphocyte DynamicsR01OD011095 · OD · TRIAD NATIONAL SECURITY, LLC · PI PERELSON, ALAN S · 2012 to 2024
$5.0M
Immune System Modeling/HIVR01AI028433 · NIAID · UNIVERSITY OF CALIF-LOS ALAMOS NAT LAB · PI PERELSON, ALAN S · 1990 to 2021
$3.7M
Modeling the HIV latent reservoir, latency reversal and immunotherapeutics for HIV cureR01AI152703 · NIAID · TRIAD NATIONAL SECURITY, LLC · PI KE, RUIAN · 2020 to 2024
$3.0M
Developing Transmissible Antivirals by Exploiting Gene-Expression CircuitryDP2OD006677 · OD · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI WEINBERGER, LEOR S · 2009 to 2009
$2.3M
Regulation of Corneal Repair by MetalloproteinasesR01EY022739 · NEI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CHAN, MATILDA F · 2013 to 2017
$2.0M
NCATS NIH HHS UL1 TR001442NEI NIH HHS P30 EY002162NEI NIH HHS R01 EY022739NIAID NIH HHS P30 AI027763NIAID NIH HHS P30 AI036214NIAID NIH HHS R01 AI028433NIAID NIH HHS R01 AI152703NIH HHS DP2 OD006677NIH HHS R01 OD011095
6 · The paper itself

Abstract

Across biological scales, gene-regulatory networks employ autorepression (negative feedback) to maintain homeostasis and minimize failure from aberrant expression. Here, we present a proof of concept that disrupting transcriptional negative feedback dysregulates viral gene expression to therapeutically inhibit replication and confers a high evolutionary barrier to resistance. We find that nucleic-acid decoys mimicking cis-regulatory sites act as "feedback disruptors," break homeostasis, and increase viral transcription factors to cytotoxic levels (termed "open-loop lethality"). Feedback disruptors against herpesviruses reduced viral replication >2-logs without activating innate immunity, showed sub-nM IC

Indexed as

Antiviral AgentsAnimalsDrug Resistance, ViralGene Expression Regulation, ViralGene Regulatory NetworksMiceSARS-CoV-2Virus ReplicationAntiviral Agentsautoregulatory circuitfeedbacknucleic acidssynthetic biologytranscriptional feedbackviral evolution

Identifiers

PMID35561685
PMCPMC9097017
OpenAlexW4280504975

What Socratic holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.