Identification of cap-dependent endonuclease inhibitors with broad-spectrum activity against bunyaviruses.
Identification of cap-dependent endonuclease inhibitors with broad-spectrum activity against bunyaviruses.
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DOI：
10.1073/pnas.2206104119
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发表时间：
2022-09-06
影响因子：
11.1
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中科院分区：
文献类型：
--
作者：
布尼亚病毒与流感病毒一样，具有帽依赖性核酸内切酶 (CEN)，可介导病毒 RNA 转录的关键帽抢夺步骤。我们鉴定了流感 CEN 抑制剂中的抗布尼亚病毒化合物，并鉴定了参与抑制机制的特定结构。这些药物在体外对布尼亚病毒（包括拉沙病毒、淋巴细胞脉络膜脑膜炎病毒 (LCMV) 和胡宁病毒）的活性比利巴韦林高 100 至 1,000 倍。在感染 LCMV 的小鼠中，这些化合物显着降低了血液病毒载量，抑制了血小板减少和肝功能障碍等症状，并提高了存活率。由于还鉴定出了针对其他布尼亚病毒（包括拉克罗斯病毒、严重发热伴血小板减少综合征病毒和汉坦病毒）的有效化合物，因此我们证明了 CEN 抑制剂在治疗病毒性出血性疾病方面的潜在临床用途。由布尼亚病毒目成员引起的病毒性出血热包括地方性和新出现的人类感染，是重大的公共卫生问题。尽管疾病严重，但可用的治疗选择很少，因此迫切需要有效的抗病毒药物来减轻疾病负担。布尼亚病毒与流感病毒 (IFV) 一样，具有帽依赖性核酸内切酶 (CEN)，可介导病毒 RNA 转录的关键帽抢夺步骤。我们从 CEN 抑制剂 (CENi) 库中筛选了化合物，并鉴定了特定结构的化合物，其体外对抗布尼亚病毒（包括拉沙病毒、淋巴细胞脉络膜脑膜炎病毒 (LCMV) 和胡宁病毒）的活性比利巴韦林高 100 至 1,000 倍。为了研究其抑制作用机制，在培养物中选择了耐药病毒。全基因组测序显示，耐药病毒 CEN 区域的氨基酸取代位置与药物选择下衍生的 IFV 的 CEN α3 螺旋环位置相似。因此，我们的研究表明CENi化合物以机制相似的方式抑制布尼亚病毒和IFV复制。结构分析表明，该化合物主结构第七位的羧基侧链对于布尼亚病毒的高抗病毒活性至关重要。在感染 LCMV 的小鼠中，这些化合物显着降低了血液病毒载量，抑制了血小板减少和肝功能障碍等症状，并提高了存活率。这些数据表明 CENis 在治疗由布尼亚病毒引起的严重流感和出血性疾病方面具有潜在的广谱临床效用。
Bunyaviruses, like influenza viruses, possess a cap-dependent endonuclease (CEN) that mediates the critical cap-snatching step of viral RNA transcription. We identified the antibunyavirus compounds among influenza CEN inhibitors and identified specific structures involved in the inhibitory mechanism. These were 100- to 1,000-fold more active in vitro than ribavirin against bunyaviruses, including Lassa virus, lymphocytic choriomeningitis virus (LCMV), and Junin virus. In LCMV-infected mice, the compounds significantly decreased blood viral load, suppressed symptoms such as thrombocytopenia and hepatic dysfunction, and improved survival rates. Since effective compounds against other bunyaviruses including La Crosse virus, severe fever with thrombocytopenia syndrome virus, and hantavirus were also identified, we demonstrated the potential clinical utility of CEN inhibitors for the treatment of viral hemorrhagic diseases. Viral hemorrhagic fevers caused by members of the order Bunyavirales comprise endemic and emerging human infections that are significant public health concerns. Despite the disease severity, there are few therapeutic options available, and therefore effective antiviral drugs are urgently needed to reduce disease burdens. Bunyaviruses, like influenza viruses (IFVs), possess a cap-dependent endonuclease (CEN) that mediates the critical cap-snatching step of viral RNA transcription. We screened compounds from our CEN inhibitor (CENi) library and identified specific structural compounds that are 100 to 1,000 times more active in vitro than ribavirin against bunyaviruses, including Lassa virus, lymphocytic choriomeningitis virus (LCMV), and Junin virus. To investigate their inhibitory mechanism of action, drug-resistant viruses were selected in culture. Whole-genome sequencing revealed that amino acid substitutions in the CEN region of drug-resistant viruses were located in similar positions as those of the CEN α3-helix loop of IFVs derived under drug selection. Thus, our studies suggest that CENi compounds inhibit both bunyavirus and IFV replication in a mechanistically similar manner. Structural analysis revealed that the side chain of the carboxyl group at the seventh position of the main structure of the compound was essential for the high antiviral activity against bunyaviruses. In LCMV-infected mice, the compounds significantly decreased blood viral load, suppressed symptoms such as thrombocytopenia and hepatic dysfunction, and improved survival rates. These data suggest a potential broad-spectrum clinical utility of CENis for the treatment of both severe influenza and hemorrhagic diseases caused by bunyaviruses.
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影响因子：
6.7
作者：
Reguera J;Gerlach P;Rosenthal M;Gaudon S;Coscia F;Günther S;Cusack S
通讯作者：
Cusack S
影响因子：
3.1
作者：
PAUWELS, R;BALZARINI, J;DECLERCQ, E
通讯作者：
DECLERCQ, E
影响因子：
4.8
作者：
Maruyama, Junki;Manning, John T.;Paessler, Slobodan
通讯作者：
Paessler, Slobodan
影响因子：
4.9
作者：
TOMASSINI, J;SELNICK, H;WOLFE, A
通讯作者：
WOLFE, A
影响因子：
7.3
作者：
Miyagawa, Masayoshi;Akiyama, Toshiyuki;Kawai, Makoto
通讯作者：
Kawai, Makoto