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Transcriptional Feedback Disruption Yields Escape-Resistant Antivirals

Sonali Chaturvedi, Marie Wolf, Noam Vardi, Kelvin Du, Joshua Glazier, Ruian Ke, Matilda F. Chan, Alan S. Perelson, Leor S. Weinberger
doi: https://doi.org/10.1101/464495
Sonali Chaturvedi
1Gladstone|UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158;
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Marie Wolf
1Gladstone|UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158;
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Noam Vardi
1Gladstone|UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158;
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Kelvin Du
1Gladstone|UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158;
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Joshua Glazier
1Gladstone|UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158;
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Ruian Ke
2Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545
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Matilda F. Chan
3Francis I. Proctor Foundation,
4Department of Ophthalmology,
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Alan S. Perelson
2Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545
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Leor S. Weinberger
1Gladstone|UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158;
5Department of Biochemistry and Biophysics
6Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158
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  • For correspondence: leor.weinberger@gladstone.ucsf.edu
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Abstract

From microbes to cancers, drug-resistant ‘escape’ variants cause significant morbidity and mortality1–7. Here we present proof-of-concept that disruption of viral auto-regulatory (feedback) circuits strongly inhibits viral replication and confers an extremely high barrier to the evolution of resistance. Using DNA duplexes, we develop single-molecule ‘feedback-circuit disruptors’ that interfere with transcriptional negative feedback in human herpesviruses (both Herpes Simplex Virus 1 and Cytomegalovirus) thereby increasing viral transcription factors to cytotoxic levels. Feedback disruptors exhibit low-nanomolar to picomolar IC-50’s, reduce viral replication >100-fold in culture and in mice, and synergize with the standard-of-care antivirals. Strikingly, no feedback-disruptor escape mutants evolved over >60 days of culture, in contrast to approved antivirals to which resistance rapidly evolved. Overall, the results demonstrate that molecular targeting of feedback circuitry could yield escape-resistant antivirals, potentially enabling development of a new class of antimicrobials.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations

    (FD)
    feedback disruptor
    (CMV)
    human cytomegalovirus
    (HSV-1)
    herpes simplex virus 1
  • Copyright 
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    Posted September 15, 2020.
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    Transcriptional Feedback Disruption Yields Escape-Resistant Antivirals
    Sonali Chaturvedi, Marie Wolf, Noam Vardi, Kelvin Du, Joshua Glazier, Ruian Ke, Matilda F. Chan, Alan S. Perelson, Leor S. Weinberger
    bioRxiv 464495; doi: https://doi.org/10.1101/464495
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    Transcriptional Feedback Disruption Yields Escape-Resistant Antivirals
    Sonali Chaturvedi, Marie Wolf, Noam Vardi, Kelvin Du, Joshua Glazier, Ruian Ke, Matilda F. Chan, Alan S. Perelson, Leor S. Weinberger
    bioRxiv 464495; doi: https://doi.org/10.1101/464495

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