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bioRxiv · 10.1101/464495

Disrupting Transcriptional Feedback Yields an Escape-Resistant Antiviral

Chaturvedi, S.·Wolf, M.·Vardi, N.·Singhal, R.·Weinberger, A. D.·Chan, M.·Weinberger, L.
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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-50s, 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.

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Chaturvedi, S., Wolf, M., Vardi, N., Singhal, R., Weinberger, A. D., Chan, M., Weinberger, L.. 2018-11-07. Disrupting Transcriptional Feedback Yields an Escape-Resistant Antiviral. https://doi.org/10.1101/464495

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