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
