Inhibitors of HIV-1 Nef-Mediated Activation of the Myeloid Src-Family Kinase Hck Block HIV-1 Replication in Macrophages and Disrupt MHC-I Downregulation.
Inhibitors of HIV-1 Nef-Mediated Activation of the Myeloid Src-Family Kinase Hck Block HIV-1 Replication in Macrophages and Disrupt MHC-I Downregulation.
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DOI：
10.1021/acsinfecdis.1c00288
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发表时间：
2022-01-14
影响因子：
5.3
通讯作者：
Smithgall, Thomas E.
中科院分区：
文献类型：
--
作者：
Emert-Sedlak, Lori A.;Moukha-Chafiq, Omar;Shi, Haibin;Du, Shoucheng;Alvarado, John J.;Pathak, Vibha;Tanner, Samuel G.;Hunter, Robert N.;Nebane, Miranda;Chen, Li;Ilina, Tatiana, V;Ishima, Rieko;Zhang, Sixue;Kuzmichev, Yury, V;Wonderlich, Elizabeth R.;Schader, Susan M.;Augelli-Szafran, Corinne E.;Ptak, Roger G.;Smithgall, Thomas E.
HIV-1 Nef是抗逆转录病毒药物开发的一个有吸引力的靶点，因为它可以促进HIV-1的感染性、复制和宿主免疫系统的避免。在这里，我们应用了一种筛选策略，将重组HIV-1Nef蛋白与Src家族酪氨酸激酶HCK的激活偶联，后者增强了巨噬细胞中HIV-1的生命周期。NEF能在体外刺激重组HCK的活性，为化学文库的筛选提供了可靠的方法。使用Nef·HCK方法对超过730,000种化合物进行高通量筛选，确定了6种独特的HIT化合物，它们通过SPR在体外直接与重组Nef结合，并在0.04至5μM范围内抑制艾滋病毒-1在原代巨噬细胞中的复制，而没有细胞毒性。在该系列的异噻唑酮支架周围合成了84个类似物，其中许多与重组Nef结合并在低至亚微摩尔范围内抑制HIV-1的感染性。该系列化合物将MHC-I恢复到感染艾滋病毒的原代细胞表面，并破坏了Nef与MHC-I的C末端尾巴和AP-1内吞运输蛋白的μ1亚单位的重组蛋白复合体。这类NEF抑制剂有可能阻止HIV-1在髓系细胞中的复制，并触发体内适应性免疫系统对HIV感染细胞的识别。描述：HIV-1 Nef结合化合物SRI-37264破坏Nef与AP-1和MHC-I的相互作用
HIV-1 Nef is an attractive target for antiretroviral drug discovery because of its roles promoting HIV-1 infectivity, replication, and host immune system avoidance. Here we applied a screening strategy in which recombinant HIV-1 Nef protein was coupled to activation of the Src-family tyrosine kinase Hck, which enhances the HIV-1 life cycle in macrophages. Nef stimulates recombinant Hck activity in vitro, providing a robust assay for chemical library screening. High-throughput screening of more than 730,000 compounds using the Nef•Hck assay identified six unique hit compounds that bound directly to recombinant Nef by SPR in vitro and inhibited HIV-1 replication in primary macrophages in the 0.04 to 5 μM range without cytotoxicity. Eighty-four analogs were synthesized around an isothiazolone scaffold from this series, many of which bound to recombinant Nef and inhibited HIV-1 infectivity in the low to submicromolar range. Compounds in this series restored MHC-I to the surface of HIV-infected primary cells and disrupted a recombinant protein complex of Nef with the C-terminal tail of MHC-I and the μ1 subunit of the AP-1 endocytic trafficking protein. Nef inhibitors in this class have the potential to block HIV-1 replication in myeloid cells and trigger recognition of HIV-infected cells by the adaptive immune system in vivo. Description: HIV-1 Nef-binding compound SRI-37264 disrupts interaction of Nef with AP-1 and MHC-I
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影响因子：
4.4
作者：
Dionne, Brandon
通讯作者：
Dionne, Brandon
影响因子：
64.5
作者：
KESTLER, HW;RINGLER, DJ;DESROSIERS, RC
通讯作者：
DESROSIERS, RC
影响因子：
16
作者：
Mossessova, E;Lima, CD
通讯作者：
Lima, CD
影响因子：
--
作者：
Fonsi, Massimiliano;Orsale, Maria V.;Mionteagudo, Edith
通讯作者：
Mionteagudo, Edith
影响因子：
3.5
作者：
Liu, Dazhi;Tian, Zhen;Yang, Cheng
通讯作者：
Yang, Cheng