Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease
Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease
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DOI：
10.1038/nm0402-386
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发表时间：
2002-04-01
期刊：
影响因子：
82.9
通讯作者：
Cordingley, MG
中科院分区：
文献类型：
--
作者：
Crute, JJ;Grygon, CA;Cordingley, MG
单纯疱疹病毒感染是显著发病的原因，并且目前使用的治疗剂主要基于抑制病毒DNA聚合酶功能的修饰的核苷类似物。为了以一种新的方式靶向这种疾病，我们已经确定并优化了单纯疱疹病毒（HSV）解旋酶-引发酶的选择性含噻唑基苯基抑制剂。最有效的化合物抑制解旋酶，引发酶和DNA依赖性ATP酶活性的酶的IC 50（50%抑制浓度）值小于100 nM。酶活性的抑制是通过稳定解旋酶-引发酶和DNA底物之间的相互作用，防止通过解旋酶或引发酶催化循环的进展。解旋酶-引发酶抑制剂也可阻止病毒复制，如病毒生长测定所示。一种化合物BILS 179 BS显示出27 nM的抗病毒生长的EC 50（抑制50%病毒生长的有效浓度），选择性指数大于2，000。还证明了对多种HSV菌株的抗病毒活性，包括对核苷类治疗耐药的菌株。最重要的是，BILS 179 BS在HSV-1和HSV-2疾病的鼠模型中具有抗HSV感染的口服活性，并且当每天的治疗频率降低或当治疗开始延迟至感染后65小时时，比阿昔洛韦更有效。这些研究验证了解旋酶-引发酶抑制剂用于治疗急性疱疹病毒感染的用途，并为优化和设计上级抗HSV剂提供了新的先导化合物。
Herpes simplex virus infections are the cause of significant morbidity, and currently used therapeutics are largely based on modified nucleoside analogs that inhibit viral DNA polymerase function. To target this disease in a new way, we have identified and optimized selective thiazolylphenyl-containing inhibitors of the herpes simplex virus (HSV) helicase-primase enzyme. The most potent compounds inhibited the helicase, the primase and the DNA-dependent ATPase activities of the enzyme with IC50 (50% inhibitory concentration) values less than 100 nM. Inhibition of the enzymatic activities was through stabilization of the interaction between the helicase-primase and DNA substrates, preventing the progression through helicase or primase catalytic cycles. Helicase-primase inhibitors also prevented viral replication as demonstrated in viral growth assays. One compound, BILS 179 BS, displayed an EC50 (effective concentration inhibiting viral growth by 50%) of 27 nM against viral growth with a selectivity index greater than 2,000. Antiviral activity was also demonstrated for multiple strains of HSV, including strains resistant to nucleoside-based therapies. Most importantly, BILS 179 BS was orally active against HSV infections in murine models of HSV-1 and HSV-2 disease and more effective than acyclovir when the treatment frequency per day was reduced or when initiation of treatment was delayed up to 65 hours after infection. These studies validate the use of helicase-primase inhibitors for the treatment of acute herpesvirus infections and provide new lead compounds for optimization and design of superior anti-HSV agents.