Identification of novel small molecule inhibitors against NS2B/NS3 serine protease from Zika virus.
Identification of novel small molecule inhibitors against NS2B/NS3 serine protease from Zika virus.
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DOI：
10.1016/j.antiviral.2016.12.016
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发表时间：
2017-03
影响因子：
7.6
通讯作者：
Johnson ME
中科院分区：
文献类型：
--
作者：
Lee H;Ren J;Nocadello S;Rice AJ;Ojeda I;Light S;Minasov G;Vargas J;Nagarathnam D;Anderson WF;Johnson ME
怀孕期间感染寨卡黄病毒似乎会增加小头畸形的风险，还会导致多种神经系统问题，例如吉兰-巴利综合征。寨卡病毒目前在中美洲和南美洲广泛传播，预计美国南部的风险将日益增加。随着全球旅行的持续和蚊媒的传播，接触寨卡病毒的速度预计会加快，但目前尚无批准的针对寨卡病毒的治疗方法。 Zika NS2B/NS3 蛋白酶因其在病毒复制中的重要作用而成为一个有吸引力的药物靶点。我们的研究通过测试 71 种 HCV NS3/NS4A 抑制剂，鉴定出几种对 Zika NS2B-NS3 蛋白酶具有抑制活性 (IC50) 和结合亲和力 (KD) 约 5-10 μM 的化合物，这些抑制剂最初是通过对 40,967 种化合物的高通量筛选发现的。随后通过竞争性表面等离子共振研究和酶动力学抑制机制分析确定了最佳化合物为竞争性抑制剂，Ki 值为 9.5 μM。我们还确定了寨卡 NS2B-NS3 蛋白酶“预开放构象”的 X 射线结构，这是任何黄病毒蛋白酶之前从未观察到的构象。这为新的基于结构的抑制剂设计提供了基础。
Zika flavivirus infection during pregnancy appears to produce higher risk of microcephaly, and also causes multiple neurological problems such as Guillain–Barré syndrome. The Zika virus is now widespread in Central and South America, and is anticipated to become an increasing risk in the southern United States. With continuing global travel and the spread of the mosquito vector, the exposure is expected to accelerate, but there are no currently approved treatments against the Zika virus. The Zika NS2B/NS3 protease is an attractive drug target due to its essential role in viral replication. Our studies have identified several compounds with inhibitory activity (IC50) and binding affinity (KD) of ∼5-10 μM against the Zika NS2B-NS3 protease from testing 71 HCV NS3/NS4A inhibitors that were initially discovered by high-throughput screening of 40,967 compounds. Competition surface plasmon resonance studies and mechanism of inhibition analyses by enzyme kinetics subsequently determined the best compound to be a competitive inhibitor with a Ki value of 9.5 μM. We also determined the X-ray structure of the Zika NS2B-NS3 protease in a “pre-open conformation”, a conformation never observed before for any flavivirus proteases. This provides the foundation for new structure-based inhibitor design.
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影响因子：
16.8
作者：
Erbel, P;Schiering, N;Hommel, U
通讯作者：
Hommel, U
影响因子：
3.8
作者：
Faye O;Freire CC;Iamarino A;Faye O;de Oliveira JV;Diallo M;Zanotto PM;Sall AA
通讯作者：
Sall AA
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
利用虚拟筛选和支架跳跃发现登革热病毒 NS2B-NS3 蛋白酶的新型小分子抑制剂
影响因子：
7.3
作者：
Deng, Jing;Li, Ning;Zhu, Weiliang
通讯作者：
Zhu, Weiliang
影响因子：
3.4
作者：
Hammamy, M. Zouhir;Haase, Caroline;Steinmetzer, Torsten
通讯作者：
Steinmetzer, Torsten