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Disrupting Transcriptional Feedback Yields an Escape-Resistant Antiviral

Sonali Chaturvedi, Marie Wolf, Noam Vardi, Matilda F. Chan, 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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Matilda F. Chan
2Francis I. Proctor Foundation, University of California, San Francisco, CA 94158
3Department of Ophthalmology, University of California, San Francisco CA 94158
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Leor S. Weinberger
1Gladstone|UCSF Center for Cell Circuitry, Gladstone Institutes San Francisco, CA 94158;
4Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158
5Department 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

Drug resistance is a substantial clinical problem, with combination therapies often the only recourse. Here, we propose a novel antiviral approach that disrupts viral auto-regulatory circuits, which limits resistance by requiring multiple viral mutations. We provide proof-of-concept that DNA-based circuit-disruptor oligonucleotide therapies (C-DOTs) interfere with transcriptional negative feedback in human herpesviruses (CMV and HSV-1) thereby increasing viral transcription factors to cytotoxic levels. C-DOTs reduce viral replication >100-fold, are effective in high-viremic conditions where existing antivirals are ineffective, and show efficacy in mice. Strikingly, no C-DOT-resistant mutants evolved in >60 days of culture, in contrast to approved herpesvirus antivirals where resistance rapidly evolved. Oligonucleotide therapies that target feedback circuits could mimic combination therapy and represent escape-resistant interventions with broad applicability to viruses, microbes, and neoplastic cells.

One Sentence Summary A single oligonucleotide breaks transcriptional feedback and mimics combination therapy to limit the emergence of antiviral resistance.

Abbreviations
(C-DOT)
circuit disrupting oligonucleotide therapy
(CMV)
human cytomegalovirus
(HSV-1)
herpes simplex virus type 1
Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted November 26, 2018.
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Disrupting Transcriptional Feedback Yields an Escape-Resistant Antiviral
Sonali Chaturvedi, Marie Wolf, Noam Vardi, Matilda F. Chan, Leor S. Weinberger
bioRxiv 464495; doi: https://doi.org/10.1101/464495
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Disrupting Transcriptional Feedback Yields an Escape-Resistant Antiviral
Sonali Chaturvedi, Marie Wolf, Noam Vardi, Matilda F. Chan, Leor S. Weinberger
bioRxiv 464495; doi: https://doi.org/10.1101/464495

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