De novo design of isopeptide bond-tethered triple-stranded coiled coils with exceptional resistance to unfolding and proteolysis: implication for developing antiviral therapeutics.
De novo design of isopeptide bond-tethered triple-stranded coiled coils with exceptional resistance to unfolding and proteolysis: implication for developing antiviral therapeutics.
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DOI：
10.1039/c5sc02220g
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发表时间：
2015-11-01
期刊：
影响因子：
8.4
通讯作者：
Liu K
中科院分区：
文献类型：
--
作者：
Wang C;Lai W;Yu F;Zhang T;Lu L;Jiang X;Zhang Z;Xu X;Bai Y;Jiang S;Liu K
异肽桥连超稳定卷曲螺旋三聚体已被重新设计为结构导向辅助剂，以指导 HIV-1 gp41 NHR 肽三聚化。 HIV-1 gp41 N 端七肽重复 (NHR) 肽的异肽键连接的三链卷曲线圈已设计为具有从头辅助剂，以指导定点三聚化交联。合理设计的三聚基序中异肽桥的存在提供了非凡的稳定性，可承受热变性和化学变性。结果，这些超稳定且折叠良好的三聚卷曲螺旋直接产生抗蛋白水解且非常有效的N-肽嵌合三聚体，在低纳摩尔范围内具有HIV-1融合抑制活性，比相应的非结构化N-肽单体更有效，并达到临床使用的T20肽（恩夫韦地）的效力。因此，这些异肽键交联的从头卷曲线圈也可用作有吸引力的支架，用于分离其他 I 类包膜病毒中的 NHR 三聚体以进行治疗干预。此外，这种异肽桥束缚策略可以扩展到干扰某些生物过程的超稳定蛋白质的构建。
Isopeptide bridge-tethered ultra-stable coiled-coil trimers have been de novo designed as structure-directing auxiliaries to guide HIV-1 gp41 NHR-peptide trimerization. Isopeptide bond-tethered triple-stranded coiled coils of HIV-1 gp41 N-terminal heptad repeat (NHR) peptides have been designed with de novo auxiliaries to guide site-directed trimerized cross-linking. The presence of isopeptide bridges in the rationally designed trimerization motifs provides extraordinary stability to withstand thermal and chemical denaturation. As a result, these ultra-stable and well-folded trimeric coiled coils direct and yield proteolysis-resistant and remarkably potent N-peptide chimeric trimers with HIV-1 fusion inhibitory activities in the low nanomolar range, much more effective than the corresponding unstructured N-peptide monomers and reaching the potency of clinically used T20 peptide (enfuvirtide). Thus, these isopeptide bond-crosslinked de novo coiled coils may also be used as attractive scaffolds for isolating NHR-trimers in other class I enveloped viruses for therapeutic intervention. Furthermore, this isopeptide bridge-tethering strategy could be extendable to the construction of ultra-stable proteins interfering with certain biological processes.
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