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- W3186831278 abstract "Abstract From microbes to cancers, drug-resistant ‘escape’ variants cause significant morbidity and mortality 1–7 . 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." @default.
- W3186831278 created "2021-08-02" @default.
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- W3186831278 date "2018-11-07" @default.
- W3186831278 modified "2023-09-24" @default.
- W3186831278 title "Transcriptional Feedback Disruption Yields Escape-Resistant Antivirals" @default.
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- W3186831278 doi "https://doi.org/10.1101/464495" @default.
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