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首页> 外文学位 >The severe acute respiratory syndrome-associated coronavirus spike protein: Identification and characterization of the fusion-inducing domains and design of fusion inhibitory peptides.
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The severe acute respiratory syndrome-associated coronavirus spike protein: Identification and characterization of the fusion-inducing domains and design of fusion inhibitory peptides.

机译：严重的急性呼吸综合征相关冠状病毒刺突蛋白：融合诱导域的鉴定和表征以及融合抑制肽的设计。

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摘要

The severe acute respiratory syndrome (SARS) epidemic of 2002--2003 resulted in 774 deaths in 29 countries worldwide. The etiological agent of SARS (SARS-CoV) was quickly identified as belonging to the family Coronaviridae. Like other CoV, SARS-CoV enters cell through fusion of the viral membrane with the target cell membrane. This process is facilitated by the viral spike (S) glycoprotein. It is believed that the S1 subunit of the SARS-CoV S protein mediates binding to the cellular receptor(s) ACE2 and/or DC209L, while the S2 subunit, a predicted class I viral fusion protein, drives the fusion reaction.; The studies presented herein further characterize the SARS-CoV S protein by identifying and characterizing the putative fusion peptide and determining the functional role of the conserved aromatic domain. The hydrophobic stretch of 19 amino acids, corresponding to residues 770--788, was shown to be the putative fusion peptide of the SARS-CoV S2 subunit. A peptide analogous to this region strongly partitioned into the membranes of lipid vesicles, adopting a beta-sheet structure, and was capable of inducing fusion and membrane permeabilization.; In addition, biophysical studies of the aromatic domains of the SARS-CoV, mouse hepatitis virus (MHV) and the human CoV OC43 S2 subunits showed that these regions also strongly partitioned into lipid membranes and induced lipid vesicle permeabilization. Based on these biophysical studies, we propose that during membrane apposition these domains function to destabilize the leaflets of the apposed viral and target cell membranes by forming a continuous hydrophobic surface track resulting in membrane fusion and subsequent viral nucleocapsid entry.; Lastly, peptides analogous to regions of the S2 subunit were tested as inhibitors of CoV infectivity. Peptides analogous to the N-terminus or to the pretransmembrane domain of the S2 subunit inhibited CoV plaque formation by 40--50%. In addition, peptides analogous to the SARS-CoV or MHV loop region inhibited viral plaque formation by >80%. This effect was dose-dependent and not attributable to the propensity of the peptides to adopt a defined secondary structure. The antiviral activity of the CoV peptides tested provides an attractive basis for the development of new peptide inhibitors for fusion proteins of other viruses.
机译：2002--2003年的严重急性呼吸道综合症（SARS）流行导致全球29个国家的774人死亡。 SARS（SARS-CoV）的病原体很快被鉴定为属于冠状病毒科。与其他CoV一样，SARS-CoV通过病毒膜与靶细胞膜融合进入细胞。病毒刺突（S）糖蛋白促进了这一过程。相信SARS-CoV S蛋白的S1亚基介导与细胞受体ACE2和/或DC209L的结合，而预测的I类病毒融合蛋白S2亚基驱动融合反应。本文提出的研究通过鉴定和表征推定的融合肽并确定保守的芳香结构域的功能来进一步表征SARS-CoV S蛋白。 19个氨基酸的疏水性片段（对应于残基770--788）被证明是SARS-CoV S2亚基的推定融合肽。类似于该区域的肽强烈地分配到脂质囊泡的膜中，具有β-折叠结构，并且能够诱导融合和膜透化。此外，对SARS-CoV，小鼠肝炎病毒（MHV）和人CoV OC43 S2亚基的芳香结构域的生物物理研究表明，这些区域也强烈地划分为脂质膜并诱导脂质囊泡通透化。基于这些生物物理研究，我们提出在膜并置过程中，这些结构域通过形成连续的疏水性表面轨道导致膜融合和随后的病毒核衣壳进入，从而使并置的病毒和靶细胞膜的小叶不稳定。最后，测试了类似于S2亚基区域的肽作为CoV感染性的抑制剂。与N端或S2亚基的跨膜前结构域类似的肽可抑制CoV斑块形成40--50％。此外，类似于SARS-CoV或MHV环区的肽可抑制病毒斑块的形成> 80％。该作用是剂量依赖性的，而不是由于肽倾向于采用确定的二级结构。测试的CoV肽的抗病毒活性为开发用于其他病毒融合蛋白的新型肽抑制剂提供了诱人的基础。

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  • 作者

    Sainz, Bruno, Jr.;

  • 作者单位

    Tulane University.;

  • 授予单位 Tulane University.;
  • 学科 Biology Microbiology.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 180 p.
  • 总页数 180
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 微生物学;
  • 关键词

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