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: 8357942
• 负责人: Michael R. Farzan
• 金额: $ 21.06万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357942
• 关键词: Antibodies; Binding; CCR5 gene; Data; Funding; Glycoproteins; Grant; HIV Envelope Protein gp120; HIV-1; Human; Infection; Inorganic Sulfates; Mediating; National Center for Research Resources; New England; Peptides; Play; Primates; Principal Investigator; Proteins; Research; Research Infrastructure; Resources; Role; Source; Tyrosine; United States National Institutes of Health; Unspecified or Sulfate Ion Sulfates; base; complementarity-determining region 3; cost; inhibiting antibody; inhibitor/antagonist; insight; mimetics; prevent; sulfation; tyrosine O-sulfate

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 HIV-1主要辅受体CCR5氨基末端的硫酸化酪氨酸在其与HIV-1包膜糖蛋白gp120结合和介导HIV-1进入的能力中起着至关重要的作用。识别gp120 CCR5结合区的人类抗体也会被酪氨酸硫化修饰，这是它们中和HIV-1所必需的。在这里，我们证明了来自其中一个抗体E51的CDR3区域的硫酸化多肽可以有效地结合gp120。这种多肽，pE51，与gp120的结合需要酪氨酸硫化，并被CD4增强，但不依赖于。四个pE51酪氨酸中的任何一个的改变，或者gp120残基420、421或422的改变对于与CCR5的结合至关重要，阻止了gp120与pE51的结合。PE51比基于CCR5氨基末端的多肽更有效地中和HIV-1，并可能作为与其他HIV-1进入的蛋白抑制剂的融合伙伴。我们的数据为CCR5氨基末端与gp120的关联提供了进一步的见解，表明在没有CD4的情况下，gp120的保守的硫酸盐结合区可被抑制剂访问，并表明CCR5的可溶性模拟可能比先前所认识的更有效。