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首页> 外文期刊>Journal of Molecular Biology >Structural evidence for effectiveness of darunavir and two related antiviral inhibitors against HIV-2 protease.
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Structural evidence for effectiveness of darunavir and two related antiviral inhibitors against HIV-2 protease.

机译：达那那韦和两种相关抗病毒抑制剂抗HIV-2蛋白酶有效性的结构性证据。

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摘要

No drug has been targeted specifically for HIV-2 (human immunodeficiency virus type 2) infection despite its increasing prevalence worldwide. The antiviral HIV-1 (human immunodeficiency virus type 1) protease (PR) inhibitor darunavir and the chemically related GRL98065 and GRL06579A were designed with the same chemical scaffold and different substituents at P2 and P2' to optimize polar interactions for HIV-1 PR (PR1). These inhibitors are also effective antiviral agents for HIV-2-infected cells. Therefore, crystal structures of HIV-2 PR (PR2) complexes with the three inhibitors have been solved at 1.2-A 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 PR2 and the inhibitors. Overall, the structures were very similar to the corresponding inhibitor complexes of PR1 with an RMSD of 1.1 A on main-chain atoms. Most hydrogen-bond and weaker C-H...O interactions with inhibitors were conserved in the PR2 and PR1 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, in agreement with relative inhibition of the two PRs. These near-atomic-resolution crystal structures verify the inhibitor potency for PR1 and PR2 and will provide the basis for the development of antiviral inhibitors targeting PR2.
机译：尽管在世界范围内其流行程度很高，但没有一种药物专门针对HIV-2（人类免疫缺陷病毒2型）感染。抗病毒HIV-1（人类免疫缺陷病毒1型）蛋白酶（PR）抑制剂darunavir以及化学相关的GRL98065和GRL06579A设计为在P2和P2'处具有相同的化学支架和不同的取代基，以优化HIV-1 PR的极性相互作用（ PR1）。这些抑制剂对于HIV-2感染的细胞也是有效的抗病毒药。因此，已经以1.2-A的分辨率解决了带有三种抑制剂的HIV-2 PR（PR2）配合物的晶体结构，以分析其抗病毒效力的分子基础。异常地，晶体在咪唑和醋酸锌缓冲液中生长，与PR2和抑制剂形成相互作用。总体而言，其结构与PR1的相应抑制剂复合物非常相似，其主链原子的RMSD为1.1A。在PR2和PR1配合物中，大多数氢键和较弱的C-H ... O与抑制剂的相互作用均得以保留，除了与水或无序侧链相互作用的微小变化外。在地瑞那韦络合物的疏水接触中观察到很小的差异，这与两个PR的相对抑制相一致。这些接近原子分辨率的晶体结构验证了PR1和PR2的抑制剂效能，并将为开发靶向PR2的抗病毒抑制剂提供基础。

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