Abstract
Across biological scales, gene-regulatory networks employ autorepression
(negative feedback) to maintain homeostasis and minimize failure from
aberrant expression. Here, we present a proof of concept that disrupting
transcriptional negative feedback dysregulates viral gene expression to
therapeutically inhibit replication and confers a high evolutionary
barrier to resistance. We find that nucleic-acid decoys mimicking
cis-regulatory sites act as “feedback disruptors,” break
homeostasis, and increase viral transcription factors to cytotoxic
levels (termed “open-loop lethality”). Feedback disruptors against
herpesviruses reduced viral replication >2-logs without activating
innate immunity, showed sub-nM IC50, synergized with standard-of-care
antivirals, and inhibited virus replication in mice. In contrast to
approved antivirals where resistance rapidly emerged, no
feedback-disruptor escape mutants evolved in long-term cultures. For
SARS-CoV-2, disruption of a putative feedback circuit also generated
open-loop lethality, reducing viral titers by >1-log, These results
demonstrate that generating open-loop lethality, via negative-feedback
disruption, may yield a class of antimicrobials with a high genetic
barrier to resistance.
