异肽键稳定的MERS-CoV融合蛋白S2亚基N端重复序列三股α螺旋的构建

Construction of Isopeptide Bridge-tethered NHR-trimeric Coiled-coil in MERS-CoV Membrane Fusion Protein

通过在天然N肽的氨基端引入可以诱导螺旋三聚体形成的人工多肽序列,并通过酰基转移反应在上述嵌合肽所形成的三股α螺旋间引入异肽键,构建了中东呼吸综合征病毒(MERS-Co V)的N-trimer模型,为MERS-Co V融合抑制剂的设计奠定了基础.

In Middle East respiratory syndrome coronavirus（ MERS-Co V） infection,the formation of a coiledcoil six-helical bundle（ 6-HB） between three C-terminal heptad repeats（ CHRs） and an N-terminal heptad repeat（ NHR） trimer of the MERS-Co V spike protein S2 subunit provided the energy necessary for virus-cell membrane fusion. Mimicry of the NHR-helical trimers in the MERS-Co V membrane fusion protein for the discovery of antiviral therapeutics hampered because of the strong aggregation properties of synthetic NHR-based peptides taken out of their parent protein structure. Herein,the article presents an efficient strategy to recapitulate MERS-Co V NHR α-helical trimers via combining the concepts of grafting the NHR-derived peptides onto an exogenous trimerization motif with stabilization of the trimeric oligomers through isopeptide bonds. The covalent bridge was introduced by an acyl transfer reaction between lysine and glutamic acid in specific amino acid sites with thio-easter modified. The designed isopeptide bridge-stabilized chimeric trimers has strong potential for the development potent MERS-Co V fusion inhibitors.