Rational Design of HIV Entry Inhibitors

HIV进入抑制剂的合理设计

• 批准号: 6929269
• 负责人: Monique Regail Ferguson
• 金额: $ 22.65万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929269
• 关键词: HIV envelope protein gp120; Staphylococcus; chimeric proteins; computer simulation; drug design /synthesis /production; drug screening /evaluation; inhibitor /antagonist; murine leukemia virus; nuclease; peptide library; protein binding; protein protein interaction; protein structure function; surface plasmon resonance; virus infection mechanism

DESCRIPTION (provided by applicant): Combination therapy, restricted to reverse transcriptase and protease inhibitors, has dramatically improved outcomes of HIV-infected patients. In spite of the initial success, the increased prevalence of HIV strains resistant to multiple FDA-approved antiretroviral drugs mandates the design of agents directed to new therapeutic targets in HIV, such as the envelope protein. HIV infection is initiated by binding of the viral envelope to CD4 at the cell membrane. This induces a conformational change in gp120 to reveal cryptic epitopes important in viral entry. In particular, interaction of gp120 V3 loop with chemokine receptors occurs after gp120 cenformational changes, when the V3 loop becomes more exposed. The V3 loop is a critical determinant for HIV tropism via its interaction with the chemokine receptor CCR5 or CXCR4, and anti-V3 loop monoclonal antibodies can be neutralizing. The VIN2 loop may be an important determinant in shielding the V3 loop and other regions essential for binding to the appropriate HIV co-receptor. Since the VIN2 and V3 domains contain critical determinants for coreceptor interactions, these loops are suitable targets for the design of small molecule inhibitors. Our goal is to identify high-affinity small peptides that target VIN2 and V3 regions that may inhibit viral entry. We plan to generate hybrid proteins containing these loops for use as targets in the selection of specific high affinity peptides from combinatorial libraries. In order to obtain peptides specific to these loops, we will generate constructs that constrain gp120 V3 or VlN2 loops grafted into regions of murine leukemia virus (MLV) envelope protein or Staphylococcal nuclease (SN), which are well-characterized scaffold proteins that can tolerate large insertions while maintaining their native structure. Phage display will be used to select high affinity peptides directed to these loops from combinatorial libraries. The affinity of phagederived peptide(s) for the VlN2 and V3 constructs will then be assayed. There is high probability that small molecules binding to these gp120 regions will disrupt viral entry, and may be used for the development of new antiretroviral drugs. Currently, peptides targeting the envelope structure have demonstrated clinical efficacy in patients resistant to other antiretroviral therapies. Since our peptides will be targeting viral structures, we expect them to have low toxicity, and no cross-resistance with the current antiretroviral drugs.

描述（由申请人提供）：限制于逆转录酶和蛋白酶抑制剂的联合治疗显著改善了HIV感染患者的结局。尽管取得了初步成功，但对多种FDA批准的抗逆转录病毒药物具有耐药性的HIV毒株的流行率增加，要求设计针对HIV中新的治疗靶点（如包膜蛋白）的药物。 HIV感染是通过病毒包膜与细胞膜上的CD4结合而启动的。这诱导了gp120的构象变化，揭示了病毒进入中重要的隐蔽表位。特别是，gp120 V3环与趋化因子受体的相互作用发生在gp120构象变化后，此时V3环变得更加暴露。V3环通过与趋化因子受体CCR5或CXCR4相互作用是HIV嗜性的关键决定因素，抗V3环单克隆抗体可以中和。VIN 2环可能是屏蔽V3环和其他与适当的HIV辅助受体结合所必需的区域的重要决定因素。由于VIN2和V3结构域含有辅助受体相互作用的关键决定因素，因此这些环是设计小分子抑制剂的合适靶点。 我们的目标是鉴定靶向VIN2和V3区域的高亲和力小肽，这些小肽可能抑制病毒进入。我们计划产生含有这些环的杂合蛋白，用作从组合文库中选择特异性高亲和力肽的靶。为了获得对这些环特异的肽，我们将产生限制移植到鼠白血病病毒（MLV）包膜蛋白或葡萄球菌核酸酶（SN）的区域中的gp120 V3或V1N2环的构建体，其是充分表征的支架蛋白，其可以耐受大的插入，同时保持其天然结构。噬菌体展示将用于从组合文库中选择针对这些环的高亲和力肽。然后测定噬菌体衍生肽对V1N2和V3构建体的亲和力。与这些gp120区域结合的小分子很可能会破坏病毒的进入，并可能用于开发新的抗逆转录病毒药物。目前，靶向包膜结构的肽已在对其他抗逆转录病毒疗法耐药的患者中显示出临床疗效。由于我们的肽将靶向病毒结构，我们期望它们具有低毒性，并且与当前的抗逆转录病毒药物没有交叉耐药性。

项目成果

Evolution of HIV resistance mutations in patients maintained on a stable treatment regimen after virologic failure.

病毒学失败后维持稳定治疗方案的患者中艾滋病毒耐药突变的演变。

• DOI: 10.1097/01.qai.0000245882.28391.0c
• 发表时间: 2006
• 期刊: Journal of acquired immune deficiency syndromes (1999)
• 作者: Goetz,MatthewBidwell;Ferguson,MoniqueR;Han,Xueliang;McMillan,Greg;StClair,Marty;Pappa,KeithA;McClernon,DanielR;O'Brien,WilliamA
• 通讯作者: O'Brien,WilliamA