Identification and characterization of potent small molecule inhibitor of hemorrhagic fever New World arenaviruses.
Identification and characterization of potent small molecule inhibitor of hemorrhagic fever New World arenaviruses.
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DOI：
10.1016/j.antiviral.2005.10.008
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发表时间：
2006-03
影响因子：
7.6
通讯作者：
Hruby DE
中科院分区：
文献类型：
--
作者：
Bolken TC;Laquerre S;Zhang Y;Bailey TR;Pevear DC;Kickner SS;Sperzel LE;Jones KF;Warren TK;Amanda Lund S;Kirkwood-Watts DL;King DS;Shurtleff AC;Guttieri MC;Deng Y;Bleam M;Hruby DE
由美国国家过敏和传染病研究所（NIAID）定义的A类沙粒病毒是可能被生物恐怖分子武器化的人类病原体。这些致命病毒中的许多需要生物安全4级（BSL-4）的所有实验室工作的遏制，这限制了传统的实验室高通量筛选（HTS）的小分子抑制剂的识别。出于这些原因，在HTS活动中使用了一种相关的BSL-2新世界沙粒病毒，Tacaribe病毒，在氨基酸水平上与Junín病毒具有67-78%的相同性，其中在Tacaribe病毒诱导的细胞病变效应（CPE）试验中筛选了约400，000种小分子化合物。在该筛选中鉴定的化合物显示出抗病毒活性和特异性，不仅针对塔卡里贝病毒，而且针对A类新世界沙粒病毒（Junín、Machupo和Guanarito）。分离出耐药变体，表明这些化合物通过抑制病毒蛋白（病毒糖蛋白（GP 2））而不是通过细胞毒性机制发挥作用。一种先导化合物ST-294已被选定用于药物开发。这种具有良好生物利用度的有效和选择性化合物在Tacaribe小鼠攻击模型中显示出保护性抗病毒功效。这一系列化合物代表了一类新的抑制剂，可能需要进一步开发，以便有可能列入战略储存。
Category A arenaviruses as defined by the National Institute of Allergy and Infectious Diseases (NIAID) are human pathogens that could be weaponized by bioterrorists. Many of these deadly viruses require biosafety level-4 (BSL-4) containment for all laboratory work, which limits traditional laboratory high-throughput screening (HTS) for identification of small molecule inhibitors. For those reasons, a related BSL-2 New World arenavirus, Tacaribe virus, 67–78% identical to Junín virus at the amino acid level, was used in a HTS campaign where approximately 400,000 small molecule compounds were screened in a Tacaribe virus-induced cytopathic effect (CPE) assay. Compounds identified in this screen showed antiviral activity and specificity against not only Tacaribe virus, but also the Category A New World arenaviruses (Junín, Machupo, and Guanarito). Drug resistant variants were isolated, suggesting that these compounds act through inhibition of a viral protein, the viral glycoprotein (GP2), and not through cellular toxicity mechanisms. A lead compound, ST-294, has been chosen for drug development. This potent and selective compound, with good bioavailability, demonstrated protective anti-viral efficacy in a Tacaribe mouse challenge model. This series of compounds represent a new class of inhibitors that may warrant further development for potential inclusion in a strategic stockpile.
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影响因子：
7.6
作者：
Charrel, RN;de Lamballerie, X
通讯作者：
de Lamballerie, X
DOI：
10.1073/pnas.221447598
发表时间：
2001-10-23
影响因子：
11.1
作者：
Lenz, O;ter Meulen, J;Garten, W
通讯作者：
Garten, W
影响因子：
7.8
作者：
Bagai, S;Lamb, RA
通讯作者：
Lamb, RA
影响因子：
7.6
作者：
Candurra, NA;Maskin, L;Damonte, EB
通讯作者：
Damonte, EB
影响因子：
7.6
作者：
ENRIA, DA;MAIZTEGUI, JI
通讯作者：
MAIZTEGUI, JI