The identification of a small molecule compound that reduces HIV-1 Nef-mediated viral infectivity enhancement.
The identification of a small molecule compound that reduces HIV-1 Nef-mediated viral infectivity enhancement.
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DOI：
10.1371/journal.pone.0027696
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Suzu S
中科院分区：
文献类型：
--
作者：
Chutiwitoonchai N;Hiyoshi M;Mwimanzi P;Ueno T;Adachi A;Ode H;Sato H;Fackler OT;Okada S;Suzu S
Nef是一种多功能的HIV-1蛋白，可加速艾滋病的进展，并通过一种尚不清楚的机制增强子代病毒的传染性。在这里，我们证明了小分子化合物2c降低了nef介导的病毒传染性增强。当添加到病毒产生细胞时，2c不影响病毒产生本身的效率。然而，在2c存在下产生的病毒的传染性明显低于对照病毒。重要的是，在Nef+野生型病毒中观察到抑制作用，而在缺乏Nef的情况下产生的病毒在富含脯氨酸的PxxP基序破坏的Nef存在时则没有，两者都显示出显著降低的内在感染性。同时，酪氨酸激酶Hck的SH3结构域（与Nef中的PxxP基序结合）的过表达也降低了病毒的感染性。重要的是，2c抑制了Hck SH3-Nef的结合，且Nef在与Hck孵育之前与2c预孵育更明显，这表明Hck SH3和2c都直接与Nef结合，并且它们的结合位点重叠。这些结果表明，2c和Hck SH3结构域抑制Nef与未知宿主蛋白的相互作用，从而降低Nef介导的感染性增强。因此，第一个抑制化合物2c是一个有价值的化学探针，可以揭示Nef增强HIV-1传染性的潜在分子机制。
Nef is a multifunctional HIV-1 protein that accelerates progression to AIDS, and enhances the infectivity of progeny viruses through a mechanism that is not yet understood. Here, we show that the small molecule compound 2c reduces Nef-mediated viral infectivity enhancement. When added to viral producer cells, 2c did not affect the efficiency of viral production itself. However, the infectivity of the viruses produced in the presence of 2c was significantly lower than that of control viruses. Importantly, an inhibitory effect was observed with Nef+ wild-type viruses, but not with viruses produced in the absence of Nef or in the presence of proline-rich PxxP motif-disrupted Nef, both of which displayed significantly reduced intrinsic infectivity. Meanwhile, the overexpression of the SH3 domain of the tyrosine kinase Hck, which binds to a PxxP motif in Nef, also reduced viral infectivity. Importantly, 2c inhibited Hck SH3-Nef binding, which was more marked when Nef was pre-incubated with 2c prior to its incubation with Hck, indicating that both Hck SH3 and 2c directly bind to Nef and that their binding sites overlap. These results imply that both 2c and the Hck SH3 domain inhibit the interaction of Nef with an unidentified host protein and thereby reduce Nef-mediated infectivity enhancement. The first inhibitory compound 2c is therefore a valuable chemical probe for revealing the underlying molecular mechanism by which Nef enhances the infectivity of HIV-1.
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