ADS-J1 Inhibits Human Immunodeficiency Virus Type 1 Entry by Interacting with the gp41 Pocket Region and Blocking Fusion-Active gp41 Core Formation
ADS-J1 Inhibits Human Immunodeficiency Virus Type 1 Entry by Interacting with the gp41 Pocket Region and Blocking Fusion-Active gp41 Core Formation
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ADS-J1 通过与 gp41 口袋区域相互作用并阻断融合活性 gp41 核心形成来抑制人类免疫缺陷病毒 1 型进入
DOI：
10.1128/aac.00670-09
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发表时间：
2009-09
影响因子：
4.9
通讯作者：
Liu SW
中科院分区：
文献类型：
--
作者：
An XL;Guo AG;Wu SG;Debnath AK;Jiang SB;Lu H;Wang HT;Xia CL;Qi Z;Li XJ;Mao QC;Liu SW
摘要我们先前利用计算机辅助分子对接技术进行了初步筛选，并采用夹心酶联免疫吸附试验(ELISA)作为二次筛选方法，鉴定了一种抗人类免疫缺陷病毒1型(抗HIV-1)小分子化合物ADS-J1。在本研究中，我们证明了ADS-J1是一种HIV-1进入抑制物，通过添加时间试验和HIV-1介导的细胞融合试验来确定。进一步的机制研究证实，ADS-J1不阻断gp120-CD4结合，并显示出与HIV-1辅助受体CXCR4的边缘相互作用。然而，通过酶联免疫吸附试验、天然聚丙烯酰胺凝胶电泳法和圆二色谱分析表明，AdS-J1抑制了病毒gp41 N端七肽重复序列(NHR)和C末端七肽重复序列(CHR)模拟的融合活性gp41核心的形成。此外，利用表面等离子体共振分析，我们发现ADS-J1可以直接与含有gp41口袋区域的三聚体多肽IQN17结合，导致IQN17的构象变化，并阻断其与短D肽PIE7的相互作用。位于gp41口袋区域的正电荷残基(K574)是ADS-J1与NHR结合的关键。这些结果表明，AdS-J1可能通过与位于囊袋区域的疏水和带正电荷的残基的疏水和离子相互作用与病毒gp41 NHR区域结合，从而阻断gp41 NHR和ChR区域之间的联系，形成融合活性gp41核心，从而抑制HIV-1介导膜融合和病毒侵入。
ABSTRACT We previously identified a small-molecule anti-human immunodeficiency virus type 1 (anti-HIV-1) compound, ADS-J1, using a computer-aided molecular docking technique for primary screening and a sandwich enzyme-linked immunosorbent assay (ELISA) as a secondary screening method. In the present study, we demonstrated that ADS-J1 is an HIV-1 entry inhibitor, as determined by a time-of-addition assay and an HIV-1-mediated cell fusion assay. Further mechanism studies confirmed that ADS-J1 does not block gp120-CD4 binding and exhibits a marginal interaction with the HIV-1 coreceptor CXCR4. However, ADS-J1 inhibited the fusion-active gp41 core formation mimicked by peptides derived from the viral gp41 N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR), as determined by ELISA, native polyacrylamide gel electrophoresis, and circular dichroism analysis. Moreover, using a surface plasmon resonance assay, we found that ADS-J1 could bind directly to IQN17, a trimeric peptide containing the gp41 pocket region, resulting in the conformational change of IQN17 and the blockage of its interaction with a short D peptide, PIE7. The positively charged residue (K574) located in the gp41 pocket region is critical for the binding of ADS-J1 to NHR. These results suggest that ADS-J1 may bind to the viral gp41 NHR region through its hydrophobic and ionic interactions with the hydrophobic and positively charged resides located in the pocket region, subsequently blocking the association between the gp41 NHR and CHR regions to form the fusion-active gp41 core, thereby inhibiting HIV-1-mediated membrane fusion and virus entry.
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影响因子：
4.8
作者：
Wexler-Cohen, Yael;Shai, Yechiel
通讯作者：
Shai, Yechiel
DOI：
10.1073/pnas.89.21.10537
发表时间：
1992-11
影响因子：
11.1
作者：
C. Wild;T. Oas;C. McDanal;D. Bolognesi;T. Matthews
通讯作者：
C. Wild;T. Oas;C. McDanal;D. Bolognesi;T. Matthews
影响因子：
7.3
作者：
Debnath, AK;Radigan, L;Jiang, SB
通讯作者：
Jiang, SB
影响因子：
64.5
作者：
Eckert, DM;Malashkevich, VN;Kim, PS
通讯作者：
Kim, PS
DOI：
--
发表时间：
2003
期刊：
--
影响因子：
--
作者：
Shibo Jiang;Kang Lin;A. Neurath
通讯作者：
Shibo Jiang;Kang Lin;A. Neurath