Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug
Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug
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DOI：
10.1093/jac/dks147
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发表时间：
2012-08-01
影响因子：
5.2
通讯作者：
Milani, Mario
中科院分区：
文献类型：
--
作者：
Mastrangelo, Eloise;Pezzullo, Margherita;Milani, Mario
黄热病病毒（YFV）是一种典型的蚊媒黄病毒，感染后会引起严重的发热性疾病，伴有出血、多器官衰竭和高死亡率。此外，近年来，由于西尼罗河病毒、登革热和日本脑炎病毒的重新出现和发病率的增加，黄病毒属得到了进一步的关注。从昆津病毒（西尼罗河病毒的澳大利亚变种）NS 3解旋酶的晶体结构出发，我们鉴定了一个新的、未开发的蛋白质位点，该位点可能参与解旋酶催化循环，因此原则上可以作为酶抑制的靶点。通过对小分子库的计算机对接，我们可以鉴定出一些对新位点具有高预测亲和力的选定化合物。在体外解旋酶/酶测定中证实了它们对来自几种黄病毒的解旋酶的活性。伊维菌素是一种广泛使用的抗蠕虫药物，被证明是一种高效的YFV复制抑制剂（EC 50值在亚纳摩尔范围内）。此外，伊维菌素抑制其他几种黄病毒（即登革热、日本脑炎和蜱传脑炎病毒）的复制，尽管效果较差。伊维菌素发挥其作用的时间点，正好与细胞内病毒RNA合成的开始，预期的分子，特异性靶向病毒解旋酶。耐受性良好的药物伊维菌素可能持有巨大的潜力，用于治疗YFV感染。此外，基于结构的优化可能导致类似物对YFV以外的黄病毒发挥有效活性。
Infection with yellow fever virus (YFV), the prototypic mosquito-borne flavivirus, causes severe febrile disease with haemorrhage, multi-organ failure and a high mortality. Moreover, in recent years the Flavivirus genus has gained further attention due to re-emergence and increasing incidence of West Nile, dengue and Japanese encephalitis viruses. Potent and safe antivirals are urgently needed.Starting from the crystal structure of the NS3 helicase from Kunjin virus (an Australian variant of West Nile virus), we identified a novel, unexploited protein site that might be involved in the helicase catalytic cycle and could thus in principle be targeted for enzyme inhibition. In silico docking of a library of small molecules allowed us to identify a few selected compounds with high predicted affinity for the new site. Their activity against helicases from several flaviviruses was confirmed in in vitro helicase/enzymatic assays. The effect on the in vitro replication of flaviviruses was then evaluated.Ivermectin, a broadly used anti-helminthic drug, proved to be a highly potent inhibitor of YFV replication (EC50 values in the sub-nanomolar range). Moreover, ivermectin inhibited, although less efficiently, the replication of several other flaviviruses, i.e. dengue fever, Japanese encephalitis and tick-borne encephalitis viruses. Ivermectin exerts its effect at a timepoint that coincides with the onset of intracellular viral RNA synthesis, as expected for a molecule that specifically targets the viral helicase.The well-tolerated drug ivermectin may hold great potential for treatment of YFV infections. Furthermore, structure-based optimization may result in analogues exerting potent activity against flaviviruses other than YFV.