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: 8172852
• 负责人: Michael R. Farzan
• 金额: $ 20.24万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172852
• 关键词: Antibodies; Binding; CCR5 gene; Computer Retrieval of Information on Scientific Projects Database; Data; 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; insight; mimetics; 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. Our data provide further insight into the association of the CCR5 amino terminus with gp120, show that a conserved, sulfate-binding region of gp120 is accessible to inhibitors in the absence of CD4, and suggest that soluble mimetics of CCR5 can be more effective than previously appreciated.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 HIV-1主要辅助受体CCR 5氨基末端的硫酸化酪氨酸在其结合HIV-1包膜糖蛋白gp 120和介导HIV- 1进入的能力中起关键作用。识别gp 120的CCR 5结合区的人抗体也通过酪氨酸硫酸化修饰，这是它们中和HIV-1的能力所必需的。在这里，我们证明，来自这些抗体之一，E51的CDR 3区的硫酸化肽，可以有效地结合gp 120。该肽pE 51与gp 120的结合需要酪氨酸硫酸化，并且通过CD 4增强，但不依赖于CD 4。四个pE 51酪氨酸中任一个的改变，或gp 120残基420、421或422的改变与CCR 5相关的关键防止gp 120与pE 51结合。pE 51比基于CCR 5氨基末端的肽更有效地中和HIV-1，并且可以用作与HIV-1进入的其它蛋白质抑制剂的融合伴侣。我们的数据提供了进一步的洞察到协会的CCR 5氨基末端与gp 120，显示一个保守的，硫酸盐结合区的gp 120是可访问的抑制剂在没有CD 4，并建议CCR 5的可溶性模拟物可以比以前认识到的更有效。