Structural evidence for effectiveness of darunavir and two related antiviral inhibitors against HIV-2 protease.
Structural evidence for effectiveness of darunavir and two related antiviral inhibitors against HIV-2 protease.
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DOI：
10.1016/j.jmb.2008.09.031
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发表时间：
2008-12-05
影响因子：
5.6
通讯作者：
Weber, Irene T.
中科院分区：
文献类型：
--
作者：
Kovalevsky, Andrey Y.;Louis, John M.;Aniana, Annie;Ghosh, Arun K.;Weber, Irene T.
尽管HIV-2在世界范围内日益流行，但目前还没有专门针对HIV-2感染的药物。抗病毒HIV-1蛋白酶抑制剂darunavir和化学相关GRL-98065和GRL-06579A采用相同的化学支架和不同的P2和P2 '取代基来优化HIV-1蛋白酶的极性相互作用。这些抑制剂也是HIV-2感染细胞的有效抗病毒药物。因此，我们以1.2 Å的分辨率解析了这三种抑制剂与HIV-2蛋白酶复合物的晶体结构，以分析其抗病毒效力的分子基础。不同寻常的是，晶体生长在咪唑和醋酸锌缓冲液中，与蛋白酶和抑制剂形成相互作用。总的来说，这些结构与HIV-1蛋白酶的相应抑制剂复合物非常相似，主链原子上的RMSD为1.1 Å。在HIV-2和HIV-1蛋白酶复合物中，除了与水或无序侧链的相互作用发生微小变化外，大多数氢键和较弱的C-H…O相互作用与抑制剂的相互作用是保守的。在达那韦复合物的疏水接触中观察到微小的差异，这与两种蛋白酶的相对抑制一致。这些近原子分辨率的晶体结构验证了HIV-1和HIV-2蛋白酶抑制剂的效力，并将为未来开发针对HIV-2蛋白酶的抗病毒抑制剂提供基础。
No drugs have been targeted specifically for HIV-2 infection despite the increasing prevalence worldwide. The antiviral HIV-1 protease inhibitor darunavir, and the chemically related GRL-98065 and GRL-06579A, were designed with the same chemical scaffold and different substituents at P2 and P2′ to optimize polar interactions for HIV-1 protease. These inhibitors are also effective antiviral agents for HIV-2 infected cells. Therefore, crystal structures of HIV-2 protease complexes with the three inhibitors have been solved at 1.2 Å resolution to analyze the molecular basis for their antiviral potency. Unusually, the crystals were grown in imidazole and zinc acetate buffer, which formed interactions with the protease and the inhibitors. Overall, the structures were very similar to the corresponding inhibitor complexes of HIV-1 protease with RMSD of 1.1 Å on main chain atoms. The majority of hydrogen bond and weaker C-H…O interactions with inhibitors were conserved in the HIV-2 and HIV-1 protease complexes, except for small changes in interactions with water or disordered side chains. Small differences were observed in the hydrophobic contacts for the darunavir complexes, which agreed with relative inhibition of the two proteases. These near-atomic resolution crystal structures verify the inhibitor potency for HIV-1 and HIV-2 proteases and will provide the basis for future development of antiviral inhibitors targeting HIV-2 protease.
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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
影响因子：
3
作者：
Brower, Evan T.;Bacha, Usman M.;Freire, Ernesto
通讯作者：
Freire, Ernesto
影响因子：
5.4
作者：
Ariën, KK;Abraha, A;Arts, EJ
通讯作者：
Arts, EJ
影响因子：
5.6
作者：
Kovalevsky, Andrey Y.;Liu, Fengling;Weber, Irene T.
通讯作者：
Weber, Irene T.
影响因子：
4.9
作者：
De Meyer, S;Azijn, H;de Béthune, MP
通讯作者：
de Béthune, MP