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Prevention of viral infection via modification of virus or cells with methoxypoly(ethylene glycol).

机译：通过用甲氧基聚乙二醇修饰病毒或细胞来预防病毒感染。

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摘要

Viral entry into cells is typically mediated by specific interactions between viral proteins and cell surface receptors. Recent pharmacological methods have attempted to exploit this specificity. For example, the interaction of rhinoviruses with ICAM-1 (its cell receptor) can be inhibited by either free zinc or soluble ICAM-1. However, this and other approaches are highly virus specific. Therefore a broad-spectrum method of preventing viral infections is needed.; One potential nonspecific method of preventing viral infections is through the modification of host cells with a nontoxic physical barrier. It is my hypothesis that this may be accomplished by the covalent derivatization of cell membranes with methoxypoly(ethylene glycol) [mPEG]. Our previous research demonstrated that covalent modification of mammalian cells with activated mPEG produced a protective barrier that functioned, in part, as a molecular sieve. While small molecules (e.g., water and glucose) readily pass through, larger molecules (e.g., antibodies), particles (e.g., immune complexes) and cells were excluded from interacting with membrane components. My study further extended these findings to models of viral pathogenesis. Five viruses were employed: Simian virus 40 [SV40], Theiler's murine encephalomyelitis virus [TMEV], mouse adenovirus [MAV], rat coronavirus [RCV] and cytomegalovirus [CMV]. Importantly, these viruses varied in mode of entry, size and structure. As demonstrated in this thesis, modification of either the virus or target cell effectively blocked viral infection. For example, cells challenged with unmodified SV40 were 47% infected at 24 hours while 4 and 0% of cells modified with 2.4 and 15 mM 5 kDa cyanuric chloride activated mPEG (CmPEG) were infected, respectively. The broad spectrum effects of mPEG grafting were demonstrated by the findings that modification of host cells with only 0.2 mM activated mPEG (5 kDa) resulted in a 95%, 78% and 47% reduction in plaque formation compared to control cells challenged with RCV, MAV and TMEV, respectively. Further studies were conducted to determine the effects of reaction time, temperature, polymer size and linker chemistry on the antiviral efficacy of mPEG gafting. In summary, these studies show that mPEG modification of viruses and/or host cells is a potent and broad spectrum method of preventing viral infection.
机译：病毒进入细胞通常是由病毒蛋白和细胞表面受体之间的特异性相互作用介导的。最近的药理方法已经尝试利用这种特异性。例如，鼻病毒与ICAM-1（其细胞受体）的相互作用可以被游离锌或可溶性ICAM-1抑制。但是，此方法和其他方法高度特定于病毒。因此，需要一种预防病毒感染的广谱方法。预防病毒感染的一种潜在的非特异性方法是通过用无毒的物理屏障修饰宿主细胞。我的假设是，可以通过用甲氧基聚（乙二醇）[mPEG]将细胞膜共价衍生化来实现。我们以前的研究表明，用活化的mPEG对哺乳动物细胞进行共价修饰会产生保护性屏障，该屏障部分充当分子筛。小分子（例如水和葡萄糖）容易通过，而大分子（例如抗体），颗粒（例如免疫复合物）和细胞则不能与膜成分相互作用。我的研究将这些发现进一步扩展到病毒发病机理模型中。使用了五种病毒：猿猴病毒40 [SV40]，泰勒氏鼠脑脊髓炎病毒[TMEV]，小鼠腺病毒[MAV]，大鼠冠状病毒[RCV]和巨细胞病毒[CMV]。重要的是，这些病毒的进入方式，大小和结构各不相同。如本论文所证明的，病毒或靶细胞的修饰有效地阻断了病毒感染。例如，用未修饰的SV40攻击的细胞在24小时被感染47％，而分别用2.4和15 mM 5 kDa氰尿酰氯激活的mPEG（CmPEG）修饰的细胞分别感染不到4％和0％。研究发现，与仅用RCV攻击的对照细胞相比，仅用0.2 mM活化的mPEG（5 kDa）修饰宿主细胞可使菌斑形成减少95％，78％和47％，从而证明了mPEG移植的广谱效应。 MAV和TMEV分别。进行了进一步的研究以确定反应时间，温度，聚合物大小和接头化学性质对mPEG灌胃的抗病毒功效的影响。总之，这些研究表明，病毒和/或宿主细胞的mPEG修饰是一种有效且广谱的预防病毒感染的方法。

著录项

  • 作者

    McCoy, Lori L.;

  • 作者单位

    The University of British Columbia (Canada).;

  • 授予单位 The University of British Columbia (Canada).;
  • 学科 Biology Microbiology.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 195 p.
  • 总页数 195
  • 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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