破坏自抑制电路产生"开放循环致死性",产生抗病毒药物
Sonali Chaturvedi1, Michael Pablo1, Marie Wolf1
1Gladstone/UCSF Center for Cell Circuitry, Gladstone Institutes, San Francisco, CA 94158, USA; Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA 94158, USA.
Cell
|May 13, 2022
概括
用核酸诱破坏基因网络的负反会导致病毒的"开放循环致命性",抑制复制. 这种新型抗菌策略显示出对疹病毒和SARS-CoV-2等病毒的高耐药性障碍.
科学领域:
- 分子生物学
- 病毒学
- 遗传学
背景情况:
- 基因调节网络利用自我抑制 (负反) 来实现平衡,并防止异常基因表达.
- 病毒复制依赖于复杂的基因调节网络,可以作为治疗干预的目标.
研究的目的:
- 调查病毒中转录负反是否可以抑制复制并建立一个高阻碍抗性.
- 通过破坏病毒平衡来证明一种名为"开放循环致死性"的新疗法.
主要方法:
- 使用模仿 cis 调节位的核酸诱来破坏病毒基因表达中的负反循环.
- 评估了病毒复制,细胞毒性,与现有抗病毒药物的协同作用,以及疹病毒和SARS-CoV-2模型的耐药性演变.
- 在感染的小鼠模型中评估治疗效果.
主要成果:
- 反干扰剂减少了疹病毒复制量超过2个日志,具有亚纳米IC50值,而没有激活先天免疫力.
- 这种方法与标准抗病毒药物协同作用,并在体内显示有效性,长期培养中没有出现耐药突变.
- 破坏SARS-CoV-2反回路也诱导了开放循环的致死率,使病毒标位减少了超过1个日志.
结论:
- 破坏负面反以产生"开放循环致死性"是抗病毒治疗的可行策略.
- 这种方法为抗药性提供了很高的遗传障碍,与目前的抗病毒限制形成鲜明对比.
- 核酸诱是一种有前途的新型抗菌药物,针对病毒基因调节.
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