Identification of inhibitors that block vaccinia virus infection by targeting the DNA synthesis processivity factor D4.
Identification of inhibitors that block vaccinia virus infection by targeting the DNA synthesis processivity factor D4.
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DOI：
10.1021/jm101554k
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发表时间：
2011-05-12
影响因子：
7.3
通讯作者：
Ricciardi RP
中科院分区：
文献类型：
--
作者：
Nuth M;Huang L;Saw YL;Schormann N;Chattopadhyay D;Ricciardi RP
天花在30年前通过接种疫苗在全球范围内被根除。最近的生物恐怖主义威胁要求开发改进的疫苗和新的治疗方法，以有效地防止天花的重新出现。一种新的治疗靶点是牛痘病毒持续合成复合物，其包含D4和A20蛋白，使病毒E9 DNA聚合酶能够合成延伸链。从旨在破坏A20：D4结合的AlphaScreen测定中鉴定的五种化合物显示出在以下方面有效：（i）体外阻断牛痘进行性DNA合成，（ii）以最小的细胞毒性预防细胞感染，以及（iii）结合D4，如ThermoFluor所证明的。抑制病毒感染性的EC 50值范围为9.6 - 23 μM，相应的选择性指数（细胞毒性CC 50/病毒感染性EC 50）为3.9 - 17.8。因此，这五种化合物是能够通过对牛痘持续合成复合物的组分的破坏性作用来停止天花DNA合成和感染性的潜在治疗剂。
Smallpox was globally eradicated 30 years ago by vaccination. The recent threat of bioterrorism demands the development of improved vaccines and novel therapeutics to effectively preclude a reemergence of smallpox. One new therapeutic target is the vaccinia poxvirus processivity complex, comprising D4 and A20 proteins that enable the viral E9 DNA polymerase to synthesize extended strands. Five compounds identified from an AlphaScreen assay designed to disrupt A20:D4 binding were shown to be effective in: (i) blocking vaccinia processive DNA synthesis in vitro, (ii) preventing cellular infection with minimal cytotoxicity, and (iii) binding to D4, as evidenced by ThermoFluor. The EC50 values for inhibition of viral infectivity ranged from 9.6 to 23 μM with corresponding selectivity indices (cytotoxicity CC50/viral infectivity EC50) of 3.9 to 17.8. The five compounds are thus potential therapeutics capable for halting smallpox DNA synthesis and infectivity through disruptive action against a component of the vaccinia processivity complex.
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