Chemoreactive-Inspired Discovery of Influenza A Virus Dual Inhibitor to Block Hemagglutinin-Mediated Adsorption and Membrane Fusion.,Journal of Medicinal Chemistry

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Chemoreactive-Inspired Discovery of Influenza A Virus Dual Inhibitor to Block Hemagglutinin-Mediated Adsorption and Membrane Fusion.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-06-10 , DOI: 10.1021/acs.jmedchem.0c00312
Guangwei Wu ₁ , Guihong Yu ₁ , Yunjia Yu ₁ , Shuang Yang ₁ , Zhongwei Duan ₁ , Wei Wang _{1,

2} , Yankai Liu ₁ , Rilei Yu ₁ , Jing Li ₁ , Tianjiao Zhu ₁ , Qianqun Gu ₁ , Dehai Li _{1,

2}

Affiliation

Owing to the emergence of drug resistance and high morbidity and mortality, the need for novel anti-influenza A virus (IAV) drugs with divergent targets is highly sought after. Herein, we reveal the discovery of an anti-IAV agent as a dual inhibitor to block hemagglutinin-mediated adsorption and membrane fusion using a chemoreactive ortho-quinone methide (o-QM) equivalent. Based on the o-QM equivalent nonenzymatically multipotent behavior, we created a series of clavatol-derived pseudo-natural products and found that penindolone (PND), a new diclavatol indole adduct, exhibited potent and broad-spectrum anti-IAV activities with low risk of inducing drug resistance. Distinct from current anti-IAV drugs, PND possesses a novel scaffold and is the first IAV inhibitor targeting both HA1 and HA2 subunits of virus hemagglutinin to dually block the IAV adsorption and membrane fusion process. More importantly, intranasal and oral administration of PND can protect mice against IAV-induced death and weight loss, superior to the effects of the clinical drug oseltamivir. Thus, the use of chemoreactive intermediates could expand our understanding of chemical diversity and aid in the development of anti-IAV drugs with novel targets.

中文翻译：

化学反应启发的甲型流感病毒双重抑制剂的发现，以阻断血凝素介导的吸附和膜融合。

由于耐药性的出现，高发病率和高死亡率，迫切需要具有不同靶标的新型抗A型流感病毒（IAV）药物。在这里，我们揭示了一种抗IAV试剂作为双重抑制剂的发现，该抑制剂可使用化学活性邻甲基醌（o -QM）等效物来阻止血凝素介导的吸附和膜融合。基于o-QM等效的非酶多能行为，我们创建了一系列由克拉瓦托衍生的假天然产物，并发现新的二氮杂吲哚吲哚加成物Penindolone（PND）具有有效且广谱的抗IAV活性，具有较低的诱导耐药性的风险。与目前的抗IAV药物不同，PND具有新型支架，并且是第一个靶向病毒血凝素的HA1和HA2亚基的IAV抑制剂，可双重阻断IAV吸附和膜融合过程。更重要的是，鼻内和口服PND可以保护小鼠免受IAV诱导的死亡和体重减轻，优于临床药物奥司他韦。因此，化学活性中间体的使用可以扩展我们对化学多样性的理解，并有助于开发具有新靶标的抗IAV药物。

更新日期：2020-07-09

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