Solution conformations of Zika NS2B-NS3pro and its inhibition by natural products from edible plants.
Solution conformations of Zika NS2B-NS3pro and its inhibition by natural products from edible plants.
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DOI：
10.1371/journal.pone.0180632
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Song J
中科院分区：
文献类型：
--
作者：
Roy A;Lim L;Srivastava S;Lu Y;Song J
最近的寨卡病毒(ZIKV)疫情与新生儿小头畸形症和格林-巴利综合征等严重的神经系统疾病有关，但不幸的是，目前还没有有效的疫苗或药物可用。寨卡病毒NS2B-NS3pro对于病毒多蛋白的蛋白质分解和病毒复制是必不可少的。因此，NS2B-NS3Pro是抗寨卡病毒药物发现/设计的一个有吸引力的目标。在这里，我们表征了连接和未连接的寨卡病毒NS2B-NS3Pro络合物的溶液构象和催化参数，发现未连接的络合物表现出良好的分散核磁共振谱。随后，通过核磁共振谱选择性同位素标记，我们证明了NS2B的C末端残基(R73-K100)在游离态下是高度无序的，没有任何稳定的三级和二级结构。与丝氨酸蛋白酶抑制物--牛胰蛋白酶抑制物(BPTI)结合后，只有极端的C末端残基(L86-K100)保持无序。此外，我们还鉴定了富含水果和蔬菜等可食用植物的五种黄酮类化合物和一种天然苯酚，它们以非竞争性方式抑制寨卡病毒NS2B-NS3Pro，其Ki从杨梅素的770 nM到芹菜素的34.02μM不等。分子对接表明，它们都结合在活性中心背面的口袋上，并阐明了它们的构效关系。我们的研究为了解寨卡病毒NS2B-NS3pro的溶液构象提供了有价值的见解，并进一步破译了其对天然产物变构抑制的敏感性。由于这些天然产物抑制剂与目前已知的活性部位抑制剂在抑制模式和化学支架方面都有根本的不同，我们的发现可能为开发更好的变构抑制剂来对抗ZIKV感染开辟了一条新的途径。
The recent Zika viral (ZIKV) epidemic has been associated with severe neurological pathologies such as neonatal microcephaly and Guillain-Barre syndrome but unfortunately no vaccine or medication is effectively available yet. Zika NS2B-NS3pro is essential for the proteolysis of the viral polyprotein and thereby viral replication. Thus NS2B-NS3pro represents an attractive target for anti-Zika drug discovery/design. Here, we have characterized the solution conformations and catalytic parameters of both linked and unlinked Zika NS2B-NS3pro complexes and found that the unlinked complex manifested well-dispersed NMR spectra. Subsequently with selective isotope-labeling using NMR spectroscopy, we demonstrated that C-terminal residues (R73-K100) of NS2B is highly disordered without any stable tertiary and secondary structures in the Zika NS2B-NS3pro complex in the free state. Upon binding to the well-characterized serine protease inhibitor, bovine pancreatic trypsin inhibitor (BPTI), only the extreme C-terminal residues (L86-K100) remain disordered. Additionally, we have identified five flavonoids and one natural phenol rich in edible plants including fruits and vegetables, which inhibit Zika NS2B-NS3pro in a non-competitive mode, with Ki ranging from 770 nM for Myricetin to 34.02 μM for Apigenin. Molecular docking showed that they all bind to a pocket on the back of the active site and their structure-activity relationship was elucidated. Our study provides valuable insights into the solution conformation of Zika NS2B-NS3pro and further deciphers its susceptibility towards allosteric inhibition by natural products. As these natural product inhibitors fundamentally differ from the currently-known active site inhibitors in terms of both inhibitory mode and chemical scaffold, our finding might open a new avenue for development of better allosteric inhibitors to fight ZIKV infection.
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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：
16.6
作者：
Hasan SS;Miller A;Sapparapu G;Fernandez E;Klose T;Long F;Fokine A;Porta JC;Jiang W;Diamond MS;Crowe JE Jr;Kuhn RJ;Rossmann MG
通讯作者：
Rossmann MG
DOI：
10.1128/genomea.00500-14
发表时间：
2014-06-05
期刊：
Genome announcements
影响因子：
--
作者：
Baronti C;Piorkowski G;Charrel RN;Boubis L;Leparc-Goffart I;de Lamballerie X
通讯作者：
de Lamballerie X
影响因子：
--
作者：
Cox, Bryan D.;Stanton, Richard A.;Schinazi, Raymond F.
通讯作者：
Schinazi, Raymond F.
影响因子：
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作者：
Fan, Xiao;Xue, Bin;Uversky, Vladimir N.
通讯作者：
Uversky, Vladimir N.