Identification and characterization of nonsubstrate based inhibitors of the essential Dengue and West Nile virus proteases
Identification and characterization of nonsubstrate based inhibitors of the essential Dengue and West Nile virus proteases
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DOI：
10.1016/j.bmc.2004.09.036
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发表时间：
2005-01-03
影响因子：
3.5
通讯作者：
Murthy, KHM
中科院分区：
文献类型：
--
作者：
Ganesh, VK;Muller, N;Murthy, KHM
黄病毒属的72个已知成员包括致命的人类病原体，如黄热病、西尼罗河病毒和登革热病毒。目前还没有已知的针对任何黄病毒的化疗，也没有针对大多数的有效疫苗。黄病毒在宿主中有共同的基因组组织和复制分子机制，其中病毒丝氨酸蛋白酶在将病毒多蛋白加工成组成多肽的过程中起着关键作用，这是病毒复制的必要步骤。以登革热丝氨酸蛋白酶与蛋白抑制剂复合的结构为模板，我们鉴定了五个化合物，它们对登革热丝氨酸蛋白酶有抑制作用。我们还描述了这些化合物对西尼罗河病毒蛋白水解酶的平行抑制活性。其中一些化合物似乎为设计更有效和更特异的登革热和西尼罗河病毒蛋白酶抑制剂提供了模板。黄病毒蛋白水解酶的序列相似性表明，此类化合物也可能抑制其他黄病毒蛋白水解酶。(C)2004爱思唯尔有限公司。保留所有权利。
The 72 known members of the flavivirus genus include lethal human pathogens such as Yellow Fever, West Nile, and Dengue viruses. There is at present no known chemotherapy for any flavivirus and no effective vaccines for most. A common genomic organization and molecular mechanisms of replication in hosts are shared by flaviviruses with a viral serine protease playing a pivotal role in processing the viral polyprotein into component polypeptides, an obligatory step in viral replication. Using the structure of the dengue serine protease complexed with a protein inhibitor as a template, we have identified five compounds, which inhibit the enzyme. We also describe parallel inhibitory activity of these compounds against the West Nile virus Protease. A few of the compounds appear to provide a template for design of more potent and specific inhibitors of the dengue and West Nile virus proteases. Sequence similarities among flaviviral proteases suggests that such compounds might also possibly inhibit other flaviviral proteases. (C) 2004 Elsevier Ltd. All rights reserved.