Rational improvement of gp41-targeting HIV-1 fusion inhibitors: an innovatively designed Ile-Asp-Leu tail with alternative conformations.
Rational improvement of gp41-targeting HIV-1 fusion inhibitors: an innovatively designed Ile-Asp-Leu tail with alternative conformations.
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靶向gp41的HIV-1融合抑制剂的合理改进：创新设计的具有替代构象的Ile-Asp-Leu尾
DOI：
10.1038/srep31983
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发表时间：
2016-09-26
影响因子：
4.6
通讯作者：
Zhang R
中科院分区：
文献类型：
--
作者：
Zhu Y;Su S;Qin L;Wang Q;Shi L;Ma Z;Tang J;Jiang S;Lu L;Ye S;Zhang R
来自HIV gp 41的C-末端七肽重复序列（HSP 41）的肽已被开发为针对HIV-1的有效融合抑制剂，但面临增强效力和稳定性的挑战。本文报道了一种基于CHR衍生肽（Trp 628 ~ Gln 653，命名为CP）的HIV-1融合抑制剂，它具有一个新的Ile-Asp-Leu尾（IDL），使抑制活性提高了100倍。并测定了人工融合肽N36-和N43-L 6-CP-IDL的晶体结构。虽然这两种融合肽的整体结构都具有典型的六螺旋束（6-HB）构型，但它们的IDL尾部采用了两种不同的构象：具有N36的单圈螺旋和具有较长N43的钩状结构。结构比较表明，钩状IDL尾部与NHR的相互作用界面大于螺旋状IDL尾部。进一步的分子动力学模拟的两个6-HB和分离的CP-IDL肽表明，钩状形式的IDL尾可以通过其结合NHR三聚体来稳定。因此，CP-IDL具有进一步开发为新的HIV融合抑制剂的潜力，该策略可广泛用于开发针对HIV和其他包膜病毒的人工融合抑制剂。
Peptides derived from the C-terminal heptad repeat (CHR) of HIV gp41 have been developed as effective fusion inhibitors against HIV-1, but facing the challenges of enhancing potency and stability. Here, we report a rationally designed novel HIV-1 fusion inhibitor derived from CHR-derived peptide (Trp628~Gln653, named CP), but with an innovative Ile-Asp-Leu tail (IDL) that dramatically increased the inhibitory activity by up to 100 folds. We also determined the crystal structures of artificial fusion peptides N36- and N43-L6-CP-IDL. Although the overall structures of both fusion peptides share the canonical six-helix bundle (6-HB) configuration, their IDL tails adopt two different conformations: a one-turn helix with the N36 and a hook-like structure with the longer N43. Structural comparison showed that the hook-like IDL tail possesses a larger interaction interface with NHR than the helical one. Further molecular dynamics simulations of the two 6-HBs and isolated CP-IDL peptides suggested that hook-like form of IDL tail can be stabilized by its binding to NHR trimer. Therefore, CP-IDL has potential for further development as a new HIV fusion inhibitor and this strategy could be widely used in developing artificial fusion inhibitors against HIV and other enveloped viruses.
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M-T钩结构增加了HIV-1融合抑制剂西夫韦肽的效力并克服了耐药性
影响因子：
5.2
作者：
Chong, Huihui;Yao, Xue;He, Yuxian
通讯作者：
He, Yuxian
影响因子：
4.8
作者：
Qi, Zhi;Shi, Weiguo;Jiang, Shibo
通讯作者：
Jiang, Shibo
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
4.8
作者：
He, Yuxian;Xiao, Yonghong;Zhang, Linqi
通讯作者：
Zhang, Linqi