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Disrupting autorepression circuitry generates "open-loop lethality" to yield escape-resistant antiviral agents.
Chaturvedi, Sonali; Pablo, Michael; Wolf, Marie; Rosas-Rivera, Daniel; Calia, Giuliana; Kumar, Arjun J; Vardi, Noam; Du, Kelvin; Glazier, Joshua; Ke, Ruian; Chan, Matilda F; Perelson, Alan S; Weinberger, Leor S.
  • Chaturvedi S; Gladstone/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.
  • Pablo M; Gladstone/UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Wolf M; Gladstone/UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Rosas-Rivera D; Gladstone/UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Calia G; Gladstone/UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Kumar AJ; Gladstone/UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Vardi N; Gladstone/UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Du K; Gladstone/UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Glazier J; Gladstone/UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Ke R; Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
  • Chan MF; Francis 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.
  • Perelson AS; Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
  • Weinberger LS; Gladstone/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; Departm
Cell ; 185(12): 2086-2102.e22, 2022 06 09.
Article in English | MEDLINE | ID: covidwho-2293192
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 IC50, synergized with standard-of-care antivirals, and inhibited virus replication in mice. In contrast to approved antivirals where resistance rapidly emerged, no feedback-disruptor escape mutants evolved in long-term cultures. For SARS-CoV-2, disruption of a putative feedback circuit also generated open-loop lethality, reducing viral titers by >1-log. These results demonstrate that generating open-loop lethality, via negative-feedback disruption, may yield a class of antimicrobials with a high genetic barrier to resistance.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Gene Expression Regulation, Viral Limits: Animals Language: English Journal: Cell Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Gene Expression Regulation, Viral Limits: Animals Language: English Journal: Cell Year: 2022 Document Type: Article