Tight-Binding Hydroxypyrazole HIV-1 Nef Inhibitors Suppress Viral Replication in Donor Mononuclear Cells and Reverse Nef-Mediated MHC-I Downregulation.
Tight-Binding Hydroxypyrazole HIV-1 Nef Inhibitors Suppress Viral Replication in Donor Mononuclear Cells and Reverse Nef-Mediated MHC-I Downregulation.
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DOI：
10.1021/acsinfecdis.9b00382
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发表时间：
2020-02-14
影响因子：
5.3
通讯作者：
Smithgall TE
中科院分区：
文献类型：
--
作者：
Shi H;Tice CM;Emert-Sedlak L;Chen L;Li WF;Carlsen M;Wrobel JE;Reitz AB;Smithgall TE
HIV-1Nef辅助因子对体内病毒生命周期至关重要，并通过下调细胞表面MHC-I促进感染细胞的免疫逃逸。此前，我们发现了直接与Nef结合的小分子，并阻断了它的许多功能，包括增强病毒的感染性和在T细胞系中的复制。这些化合物还可以恢复艾滋病患者感染HIV的CD4T细胞表面MHC-I的表达，使其能够被自体CTL识别和杀伤。在这项研究中，我们描述了基于原始的羟基吡唑Nef抑制剂核心的一系列不同类似物的合成和评价。所有类似物通过表面等离子共振(SPR)筛选与重组HIV-1Nef的相互作用以及在感染HIV-1的TZM-bl报告细胞中的抗逆转录病毒活性。活性类似物根据结合SPR数据的三个方面(亲和力、停留时间和结合程度)与抗逆转录病毒活性的活性得分进行排名。得分最高的化合物通过SPR与Nef紧密结合，Kd值在低Nm到Pm范围内，并表现出与Nef目标非常缓慢的解离。这些类似物还抑制了IC50在1-10 nM范围内的供者PBMC中的HIV-1复制，没有细胞毒性，抑制了Nef介导的ITK和HCK酪氨酸激酶的激活，并挽救了Nef转基因T细胞中MHC-I的下调。基于这里定义的构效关系的Nef抑制剂的开发有望成为抗逆转录病毒治疗的新方法，其中包括通过适应性免疫反应根除艾滋病毒感染细胞的途径。
The HIV-1 Nef accessory factor is critical to the viral life cycle in vivo and promotes immune escape of infected cells via downregulation of cell-surface MHC-I. Previously we discovered small molecules that bind directly to Nef and block many of its functions, including enhancement of viral infectivity and replication in T cell lines. These compounds also restore cell-surface MHC-I expression in HIV-infected CD4 T cells from AIDS patients, enabling recognition and killing by autologous CTLs. In this study, we describe the synthesis and evaluation of a diverse set of analogs based on the original hydroxypyrazole Nef inhibitor core. All analogs were screened for interaction with recombinant HIV-1 Nef by surface plasmon resonance (SPR) and for antiretroviral activity in TZM-bl reporter cells infected with HIV-1. Active analogs were ranked based on an activity score that integrates three aspects of the SPR data (affinity, residence time, and extent of binding) with antiretroviral activity. The top scoring compounds bound tightly to Nef by SPR, with KD values in the low nM to pM range, and displayed very slow dissociation from their Nef target. These analogs also suppressed HIV-1 replication in donor PBMCs with IC50 values in the 1–10 nM range without cytotoxicity, inhibited Nef-mediated Itk and Hck tyrosine kinase activation, and rescued MHC-I downregulation in a Nef-transfected T cell line. Development of Nef inhibitors based on the structure-activity relationships defined here have promise as a new approach to antiretroviral therapy that includes a path to eradication of HIV-infected cells via the adaptive immune response.
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影响因子：
64.5
作者：
Lee, CH;Saksela, K;Kuriyan, J
通讯作者：
Kuriyan, J
影响因子：
3.3
作者：
Foster, John L.;Garcia, J. Victor
通讯作者：
Garcia, J. Victor
DOI：
10.1073/pnas.94.9.4653
发表时间：
1997-04-29
影响因子：
11.1
作者：
Gervaix, A;West, D;Corbeil, J
通讯作者：
Corbeil, J
影响因子：
3.4
作者：
Ali, Akbar;Wang, Jinhua;Nathans, Robin S.;Cao, Hong;Sharova, Natalia;Stevenson, Mario;Rana, Tariq M.
通讯作者：
Rana, Tariq M.
影响因子：
16.8
作者：
Jia, Xiaofei;Singh, Rajendra;Homann, Stefanie;Yang, Haitao;Guatelli, John;Xiong, Yong
通讯作者：
Xiong, Yong