ADS-J1 inhibits HIV-1 infection and membrane fusion by targeting the highly conserved pocket in the gp41 NHR-trimer
ADS-J1 inhibits HIV-1 infection and membrane fusion by targeting the highly conserved pocket in the gp41 NHR-trimer
复制标题
ADS-J1 通过靶向 gp41 NHR 三聚体中高度保守的口袋来抑制 HIV-1 感染和膜融合
DOI：
10.1016/j.bbamem.2013.12.022
复制
发表时间：
2014-05-01
影响因子：
3.4
通讯作者：
Jiang, Shibo
中科院分区：
文献类型：
--
作者：
Yu, Fei;Lu, Lu;Jiang, Shibo
我们以前确定了一种有效的小分子人类免疫缺陷病毒1型（HIV-1）融合抑制剂，称为ADS-J1，并假设它主要针对gp 41 N-末端七肽重复（NHR）三聚体中的疏水口袋。然而，这一假设受到了挑战的事实，ADS-J1不能诱导耐药突变的gp 41口袋区。因此，我们在本文中表明，HIV-1突变体对T2635（一种衍生自gp 41 C-末端七肽重复（Heptad repeat，HPTR）区域的肽，具有口袋结合结构域（pocket-binding domain，PBD））具有抗性，也对ADS-J1具有抗性。我们还表明，在gp 41口袋区域的位置64和67处具有突变的假病毒对ADS-J1和04（另一种具有PBD的CHR肽）具有高度抗性，但对T20（一种不具有PBD的CHR肽）相对敏感。ADS-J1可以有效地结合N36 Fd，N36 Fd是gp 41 NHR-三聚体的模拟物，具有暴露的口袋，并阻断C34与N36 Fd三聚体的结合以形成六螺旋束（6-HB）。然而，ADS-J1在结合具有gp 41口袋区域中的突变的N36 Fd三聚体（例如N36（Q64 A）Fd、N36（Q64 L）Fd、N36（A67 G）Fd、N36（A67 S）Fd和N36（Q66 R）Fd）方面不太有效，并且在阻断C34和这些突变N36 Fd三聚体之间的6-HB形成方面不太有效。这些结果证实了ADS-J1主要靶向HIV-1 gp 41 NHR三聚体中的口袋区域，并表明其可用作开发小分子HIV融合抑制剂的先导和作为研究gp 41介导的膜融合机制的分子探针。(C)2013 Elsevier B. V.保留所有权利。
We previously identified a potent small-molecule human immunodeficiency virus type 1 (HIV-1) fusion inhibitor, termed ADS-J1, and hypothesized that it mainly targeted the hydrophobic pocket in the gp41 N-terminal heptad repeat (NHR) trimer. However, this hypothesis has been challenged by the fact that ADS-J1 cannot induce drug-resistance mutation in the gp41 pocket region. Therefore, we show herein that HIV-1 mutants resistant to T2635, a peptide derived from the gp41 C-terminal heptad repeat (CHR) region with pocket-binding domain (PBD), were also resistant to ADS-J1. We also show that pseudoviruses with mutations at positions 64 and 67 in the gp41 pocket region were highly resistant to ADS-J1 and 04, another CHR-peptide with PBD, but relatively sensitive to T20, a CHR-peptide without PBD. ADS-J1 could effectively bind to N36Fd, a mimic of the gp41 NHR-trimer with pocket exposed, and block binding of C34 to N36Fd trimer to form six-helix bundle (6-HB). However, ADS-J1 was less effective in binding to N36Fd trimer with mutations in the gp41 pocket region, such as N36(Q64A)Fd, N36(Q64L)Fd, N36(A67G)Fd, N36(A67S)Fd, and N36(Q66R)Fd, as well as less effective in blocking 6-HB formation between C34 and these mutant N36Fd trimers. These results confirm that ADS-J1 mainly targets the pocket region in the HIV-1 gp41 NHR trimer and suggest that it could be used as a lead for developing small-molecule HIV fusion inhibitors and as a molecule probe for studying the mechanisms of gp41-mediated membrane fusion. (C) 2013 Elsevier B.V. All rights reserved.