Nov 7, 2018

Disrupting Transcriptional Feedback Yields an Escape-Resistant Antiviral

BioRxiv : the Preprint Server for Biology
Sonali ChaturvediMatilda Chan

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.

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Mentioned in this Paper

Antivirals, topical
Virus
Combination Drug Therapy
Simplexvirus
Neoplastic Cell
Human herpesvirus 1 antibody
Human herpesvirus 1
Transcription, Genetic
Virus Replication
Mutant Proteins

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