Identification of novel chemical compounds targeting filovirus VP40-mediated particle production
Identification of novel chemical compounds targeting filovirus VP40-mediated particle production
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鉴定针对丝状病毒 VP40 介导的颗粒产生的新型化合物
DOI：
10.1016/j.antiviral.2022.105267
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发表时间：
2022
影响因子：
7.6
通讯作者：
Yasuda Jiro
中科院分区：
文献类型：
--
作者：
Urata Shuzo;Omotuyi Olaposi Idowu;Izumisawa Ayako;Ishikawa Takeshi;Mizuta Satoshi;Sakurai Yasuteru;Mizutani Tatsuaki;Ueda Hiroshi;Tanaka Yoshimasa;Yasuda Jiro
埃博拉病毒（EBOV）VP40在新生病毒体组装和从感染的宿主细胞出芽中的中心作用使其成为重要的治疗靶标。在VP40寡聚化之后导致病毒样颗粒（VLP）产生的二聚化机制从未被研究用于开发针对埃博拉疾病的治疗候选物。基于分子动力学的计算筛选靶向VP40二聚体的4000万个化合物，筛选出374个化合物。Novelin体外筛选测定选择了两种化合物NUSU#1和NUSU#2。常规VLP测定一致地显示两种化合物抑制EBOV VP40介导的VLP产生。有趣的是，NUSU#1抑制其他埃博拉病毒物种和马尔堡病毒中VP 40介导的VLP产生，但不抑制拉沙病毒Z介导的VLP产生。这些结果强烈表明，所选化合物是通过破坏VP40介导的颗粒产生来对抗丝状病毒病的潜在先导药物候选物。
The central role of Ebola virus (EBOV) VP40 in nascent virion assembly and budding from infected host cells makes it an important therapeutic target. The mechanism of dimerization, following oligomerization of VP40 leading to the production of virus-like particles (VLP) has never been investigated for the development of therapeutic candidates against Ebola disease. Molecular dynamics-based computational screening targeted VP40 dimer with 40,000,000 compounds selected 374 compounds. A novelin vitroscreening assay selected two compounds, NUSU#1 and NUSU#2. Conventional VLP assays consistently showed that both compounds inhibited EBOV VP40-mediated VLP production. Intriguingly, NUSU#1 inhibited the VP40-mediated VLP production in other ebolavirus species and the Marburg virus, but did not inhibit Lassa virus Z-mediated VLP production. These results strongly suggested that the selected compounds are potential lead drug candidates against Filovirus disease via disruption of VP40-mediated particle production.