TYROSINE-SULFATED PEPTIDE DERIVED FROM HIV-1 ANTIBODY INHIBITS HIV-1 INFECTION

HIV-1 抗体衍生的酪氨酸硫酸肽可抑制 HIV-1 感染

• 批准号: 7715523
• 负责人: Michael R. Farzan
• 金额: $ 3.24万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-05 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715523
• 关键词: Antibodies; Binding; CCR5 gene; Computer Retrieval of Information on Scientific Projects Database; Funding; Glycoproteins; Grant; HIV; HIV Envelope Protein gp120; HIV-1; Human; Infection; Inorganic Sulfates; Institution; Mediating; Peptides; Play; Proteins; Research; Research Personnel; Resources; Role; Source; Tyrosine; United States National Institutes of Health; Unspecified or Sulfate Ion Sulfates; base; complementarity-determining region 3; inhibiting antibody; inhibitor/antagonist; sulfation; tyrosine O-sulfate

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Sulfated tyrosines at the amino terminus of the principal HIV-1 coreceptor CCR5 play acritical role in its ability to bind the HIV-1 envelope glycoprotein gp120 and mediate HIV- 1 entry. Human antibodies that recognize the CCR5-binding region of gp120 are also modified by tyrosine sulfation, which is necessary for their ability to neutralize HIV-1. Here we demonstrate that a sulfated peptide derived from the CDR3 region of one of these antibodies, E51, can efficiently bind gp120. Association of this peptide, pE51, with gp120 requires tyrosine sulfation, and is enhanced by, but not dependent on, CD4. Alteration of any of four pE51 tyrosines, or alteration of gp120residues 420, 421, or 422critical for association with CCR5prevents gp120 association with pE51. pE51 neutralizes HIV-1 more effectively than peptides based on the CCR5 amino terminus, and may be useful as a fusion partner with other protein inhibitors of HIV-1 entry.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 主要 HIV-1 辅助受体 CCR5 氨基末端的硫酸化酪氨酸在其结合 HIV-1 包膜糖蛋白 gp120 和介导 HIV-1 进入的能力中发挥着关键作用。识别 gp120 的 CCR5 结合区的人类抗体也经过酪氨酸硫酸化修饰，这对于它们中和 HIV-1 的能力是必需的。在这里，我们证明源自这些抗体之一 E51 的 CDR3 区的硫酸化肽可以有效结合 gp120。这种肽 pE51 与 gp120 的结合需要酪氨酸硫酸化，并且由 CD4 增强，但不依赖于 CD4。 pE51 四个酪氨酸中任何一个的改变，或对与 CCR5 关联至关重要的 gp120 残基 420、421 或 422 的改变会阻止 gp120 与 pE51 的关联。 pE51 比基于 CCR5 氨基末端的肽更有效地中和 HIV-1，并且可用作与 HIV-1 进入的其他蛋白质抑制剂的融合伴侣。