SCREENS FOR IDENTIFYING HIV FUSION INHIBITORS

用于识别 HIV 融合抑制剂的筛选

• 批准号: 2004285
• 负责人: DENNIS M LAMBERT
• 金额: $ 36.49万
• 依托单位: TRIMERIS, INC.
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2004285
• 关键词: HIV envelope protein gp41; Macaca fascicularis; antiviral agents; biological products; cell fusion; chemical registry /resource; chimeric proteins; drug screening /evaluation; enzyme linked immunosorbent assay; immunoglobulins; laboratory rat; peptide chemical synthesis; pharmacokinetics; protein purification; recombinant proteins; synthetic peptide

A synthetic peptide, T2O, representing a discrete region of the HlV fusion protein, gp4l, effectively blocks virus-mediated cell to cell fusion as well as de novo virus infection of T-cells. While T20 is promising as a peptide therapeutic, it could exhibit a limited delivery profile characteristic of peptide therapeutics. T20 binds selectively to soluble forms of HIV-1 gp4l from which it was derived. Using the screening assays developed in Phase I, we have identified more active peptides from which a T20 backup peptide will be chosen. In order to ultimately identify compounds having oral availability, we will use these screening assays to find a small molecule mimic of T2O inhibition of HIV-1 fusion and infection. The long term objectives of this proposal are to discover and develop a novel class of antivirals for the treatment of HIV infection and AIDS. We propose to develop a high through-put biochemical screen based on the binding of T20 to gp4l analogs as a first step in identifying new antiviral leads. Our specific aims are: (1) To select a second generation lead antiviral peptide with improved activity against HIV. (2) To screen a minimum of 100,000 additional compounds derived from highly diverse synthetic chemical libraries with automated antibody-based and direct binding assays. (3) To establish a partnership with at least one commercial entity possessing large diverse chemical and/or natural products libraries. (4) To determine antifusion activity of small molecule screening assay "hits" in viral and cell-based fusion assays. (5) To implement preclinical development plan after selection of lead peptide or small molecule compound(s). PROPOSED COMMERCIAL APPLICATION: The objectives set forth in this proposal are designed to identify a novel class of viral therapeutics targeted to HIV fusion which will have utility in the treatment of HlV infection in AIDS. Currently approved therapies for HIV infection target the viral RT and protease. Inhibitors of viral fusion would be mechanistically distinct from approved HlV antivirals and could find utility as both stand alone therapy and combination therapy with existing drugs.

一种合成肽T2 O，代表HIV融合蛋白的一个离散区域， 蛋白质gp 4l有效地阻断病毒介导的细胞与细胞融合， 以及T细胞的从头病毒感染。 虽然T20作为一个有前途的 肽治疗剂，它可以表现出有限的输送曲线， 肽疗法的特征。T20选择性结合可溶性 HIV-1 gp 4l是由其衍生的。使用筛选试验 在第一阶段开发的，我们已经确定了更多的活性肽， 选择T20备用肽。 为了最终确定 对于具有口服利用度的化合物，我们将使用这些筛选试验来 发现T2 O抑制HIV-1融合的小分子模拟物， 感染 该提案的长期目标是发现和 开发一种新的抗病毒药物用于治疗HIV感染， 艾滋病我们建议开发一种高通量的生化筛选， T20与gp 4l类似物的结合作为鉴定新的 抗病毒的线索 我们的具体目标是：（1）选择第二代 具有改进抗HIV活性的先导抗病毒肽。(2)筛选 至少100，000种额外的化合物， 具有自动化的基于抗体和直接 结合测定。(3)与至少一个商业伙伴建立合作关系 拥有大量不同化学和/或天然产物库的实体。 (4)确定小分子筛选试验的抗融合活性 在基于病毒和细胞的融合测定中的“命中”。(5)实施临床前 先导肽或小分子筛选后的开发计划 化合物。 建议的商业应用：本建议书中规定的目标 旨在识别一类新型病毒疗法，目标是 HIV融合体将在治疗HIV感染中具有实用性， 艾滋病目前批准的HIV感染治疗靶向病毒RT 和蛋白酶。病毒融合的抑制剂在机制上是不同的 从批准的艾滋病毒抗病毒药物，并可以找到效用，因为这两个独立 治疗和与现有药物的联合治疗。