美国加州大学旧金山分校Leor S. Weinberger、Sonali Chaturvedi等研究人员合作发现，破坏自抑制回路会产生"开环致死性"从而产生耐逃逸的抗病毒制剂。相关论文于2022年5月12日在线发表在国际学术期刊《细胞》上。
研究人员提出了一个概念性证明，破坏转录负反馈会使病毒基因表达失调，进而治疗性地抑制复制，并赋予抗性一个高进化的障碍。研究人员发现，模仿顺式调控位点的核酸诱饵作为"反馈破坏者"打破了平衡，使病毒转录因子增加到细胞毒性水平（称为"开环致死性"）。针对疱疹病毒的反馈破坏者在不激活先天免疫的情况下减少了病毒复制>2-logs，显示出低于nM的IC50，与标准抗病毒药物协同作用，并抑制小鼠的病毒复制。与已获批准的抗病毒药物相比，在长期培养中没有出现反馈破坏者逃逸突变体。
对于SARS-CoV-2来说，破坏一个假定的反馈回路也会产生开环致死性，使病毒滴度降低>1-log。这些结果表明，通过负反馈破坏产生开环致死性，可能会产生一类具有高抗性遗传屏障的抗菌药。
据悉，在整个生物尺度上，基因调控网络采用自抑制（负反馈）来维持平衡，并尽量减少异常表达带来的失败。
附：英文原文
Title: Disrupting autorepression circuitry generates “open-loop lethality” to yield escape-resistant antiviral agents
Author: Sonali Chaturvedi, Michael Pablo, Marie Wolf, Daniel Rosas-Rivera, Giuliana Calia, Arjun J. Kumar, Noam Vardi, Kelvin Du, Joshua Glazier, Ruian Ke, Matilda F. Chan, Alan S. Perelson, Leor S. Weinberger
Issue&Volume: 2022-05-12
Abstract: Across biological scales, gene-regulatory networks employ autorepression (negativefeedback) to maintain homeostasis and minimize failure from aberrant expression. Here,we present a proof of concept that disrupting transcriptional negative feedback dysregulatesviral gene expression to therapeutically inhibit replication and confers a high evolutionarybarrier 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”). Feedbackdisruptors against herpesviruses reduced viral replication >2-logs without activatinginnate immunity, showed sub-nM IC50, synergized with standard-of-care antivirals, and inhibited virus replication inmice. In contrast to approved antivirals where resistance rapidly emerged, no feedback-disruptorescape mutants evolved in long-term cultures. For SARS-CoV-2, disruption of a putativefeedback circuit also generated open-loop lethality, reducing viral titers by >1-log.These results demonstrate that generating open-loop lethality, via negative-feedbackdisruption, may yield a class of antimicrobials with a high genetic barrier to resistance.
DOI: 10.1016/j.cell.2022.04.022
Source: https://www.cell.com/cell/fulltext/S0092-8674(22)00469-X