Site-specific Isopeptide Bridge Tethering of Chimeric gp41 N-terminal Heptad Repeat Helical Trimers for the Treatment of HIV-1 Infection.
Site-specific Isopeptide Bridge Tethering of Chimeric gp41 N-terminal Heptad Repeat Helical Trimers for the Treatment of HIV-1 Infection.
复制标题
用于治疗 HIV-1 感染的嵌合 gp41 N 端七肽重复螺旋三聚体的位点特异性异肽桥束缚
DOI：
10.1038/srep32161
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发表时间：
2016-08-26
影响因子：
4.6
通讯作者：
Liu K
中科院分区：
文献类型：
--
作者：
Wang C;Li X;Yu F;Lu L;Jiang X;Xu X;Wang H;Lai W;Zhang T;Zhang Z;Ye L;Jiang S;Liu K
当在非凝集的三聚体盘绕螺旋构构中，通过引入外源性三氧化基序和分子间的二硫键键，源自HIV-1 GP41的N末端Heptad重复（NHR）可以是对病毒进入的有效抑制剂。我们最近发现，从头螺旋螺旋体内的连接异肽桥增加了对展开的特殊耐药性。在本文中，我们试图通过将特定于位点特异性的螺旋间异肽键合成为氧化还原敏感的二硫化物替代物来优化（CCIZN17）3，这是一种代表性的二硫键粘合式嵌合NHR-Trimer。在此过程中，我们系统地研究了辅助三聚体盘绕螺旋基序和NHR片段对这些NHR训练的抗病毒效能的影响。令人愉悦的是，（IZ14N24N）3具有对HIV-1感染的有前途的抑制活性，相对于其二硫键螺旋的对应物，蛋白水解稳定性显着提高，这表明作为治疗HIV-1感染的有效抗病毒剂的进一步发展的良好潜力。
Peptides derived from the N-terminal heptad repeat (NHR) of HIV-1 gp41 can be potent inhibitors against viral entry when presented in a nonaggregating trimeric coiled-coil conformation via the introduction of exogenous trimerization motifs and intermolecular disulfide bonds. We recently discovered that crosslinking isopeptide bridges within thede novohelical trimers added exceptional resistance to unfolding. Herein, we attempted to optimize (CCIZN17)3, a representative disulfide bond-stabilized chimeric NHR-trimer, by incorporating site-specific interhelical isopeptide bonds as the redox-sensitive disulfide surrogate. In this process, we systematically examined the effect of isopeptide bond position and molecular sizes of auxiliary trimeric coiled-coil motif and NHR fragments on the antiviral potency of these NHR-trimers. Pleasingly, (IZ14N24N)3possessed promising inhibitory activity against HIV-1 infection and markedly increased proteolytic stability relative to its disulfide-tethered counterpart, suggesting good potential for further development as an effective antiviral agent for treatment of HIV-1 infection.