Development of broad-spectrum enterovirus antivirals based on quinoline scaffold
Development of broad-spectrum enterovirus antivirals based on quinoline scaffold
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DOI：
10.1016/j.bioorg.2020.103981
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发表时间：
2020-08-01
影响因子：
5.1
通讯作者：
Wang, Jun
中科院分区：
文献类型：
--
作者：
Musharrafieh, Rami;Kitamura, Naoya;Wang, Jun
非脊髓灰质炎肠道病毒如肠道病毒A71（EV-A71）、EV-D 68和柯萨奇病毒B3（CVB 3）是重要的人类病原体，其疾病表现从轻微的流感样症状到更严重的脑炎、心肌炎、急性弛缓性麻痹/心肌炎，甚至死亡。目前没有有效的抗病毒药物来预防或治疗非脊髓灰质炎肠道病毒感染。在这项研究中，我们报告了我们在开发针对这些非脊髓灰质炎肠道病毒的强效和广谱抗病毒药物方面的进展。从我们先前去乙酰化的对EV-D 68具有有效抗病毒活性的先导化合物开始，我们合成了43种类似物，并分析了它们对其他EV-D 68、EV-A71和CVB 3病毒的广谱抗病毒活性。还选择了有前途的候选物用于小鼠微粒体稳定性试验，以优先考虑用于未来体内小鼠模型研究的先导化合物。总的来说，这个多参数优化过程揭示了一种有前途的先导化合物6aw，其对两种EV-D 68菌株（US/KY和US/ MO）、两种EV-A71菌株（Tainan和US/AK）和一种CVB 3菌株显示出个位数至亚微摩尔的EC 50值，具有高选择性指数。令人鼓舞的是，6aw在小鼠微粒体中稳定，半衰期为114.7分钟。总体而言，6aw是针对非脊髓灰质炎肠道病毒的最有效的广谱抗病毒药物之一，使其成为具有翻译潜力的非脊髓灰质炎肠道病毒的有前途的主要候选药物。
Non-polio enteroviruses such as enterovirus A71 (EV-A71), EV-D68, and coxsackievirus B3 (CVB3) are sig-nificant human pathogens with disease manifestations ranging from mild flu-like symptoms to more severe encephalitis, myocarditis, acute flaccid paralysis/myelitis, and even death. There is currently no effective an-tivirals to prevent or treat non-polio enterovirus infection. In this study, we report our progress in developing potent and broad-spectrum antivirals against these non-polio enteroviruses. Starting from our previously de-veloped lead compounds that had potent antiviral activity against EV-D68, we synthesized 43 analogs and profiled their broad-spectrum antiviral activity against additional EV-D68, EV-A71, and CVB3 viruses. Promising candidates were also selected for mouse microsomal stability test to prioritize lead compounds for future in vivo mouse model studies. Collectively, this multi-parameter optimization process revealed a promising lead com-pound 6aw that showed single-digit to submicromolar EC50 values against two EV-D68 strains (US/KY and US/ MO), two EV-A71 strains (Tainan and US/AK), and one CVB3 strain, with a high selectivity index. Encouragingly, 6aw was stable in mouse microsomes with a half-life of 114.7 min. Overall, 6aw represents one of the most potent broad-spectrum antiviral against non-polio enteroviruses, rendering it a promising lead candidate for non-polio enteroviruses with translational potential.