Small molecule inhibitors of enveloped virus entry

有包膜病毒进入的小分子抑制剂

• 批准号: 9011996
• 负责人: Sean PJ Whelan
• 金额: $ 535.76万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9011996
• 关键词: Address; Amantadine; Animal Disease Models; Antiviral Agents; Arthropods; Binding; CCR5 gene; Case Fatality Rates; Categories; Cells; Clinical; Dengue; Dengue Virus; Ebola virus; Enzymes; Filovirus; Flavivirus; Frankfurt-Marburg Syndrome Virus; Goals; HIV-1; Human; Influenza A virus; Instruction; Ion Channel; Licensing; Membrane Fusion; Proteins; Research Personnel; Ribonucleoproteins; T-20; Testing; Therapeutic; Translational Research; Viral; Viral Envelope Proteins; Virus; West Nile virus; Work; Yellow fever virus; cellular targeting; env Gene Products; gp-120 Antigen; inhibitor/antagonist; neutralizing antibody; pathogen; prevent; programs; receptor; small molecule; small molecule inhibitor; synthetic peptide; therapeutic target; trafficking; uptake

The goal of this Center for Excellence in Translational Research is to develop small molecule inhibitors of enveloped virus entry and test their efficacy in animal models of disease. The underlying hypothesis is that enveloped viral entry is replete with therapeutic targets to which small molecule inhibitors can be developed, blocking receptor engagement, membrane fusion, and cellular trafficking. Most classes of licensed antiviral drugs block intracellular steps of the replication cycle, often through interfering with virally encoded enzymes required for replication. A handful of antiviral agents block enveloped virus entry: maraviroc, a small-molecule that blocks engagement of the CCR5 co-receptor by gp 120 of human immunodeficiency virus-1; enfuvirtide, a synthetic peptide that binds gp41 of HIVI and interferes with fusion; and amantadine/rimantidine. which blocks the M2 ion channel of certain strains of influenza A virus to prevent release of the viral ribonucleoprotein segments into the cell. That paucity of synthetic entry inhibitors starkly contrasts with the natural protection mechanism of neutralizing antibodies that frequently block viral entry. This CETR will advance two general approaches to small molecule inhibition of viral entry: direct targeting of viral envelope proteins; and specific targeting of cellular factors requisite for infectious virus entry. Targeting envelope proteins has the advantage that the small molecules do not need to enter cells, thus eliminating uptake and potential export concerns, and such inhibitors may be less likely to have unwanted interactions with cellular proteins. Targeting cellular proteins offers the attractive though unproven possibility to inhibit the entry of multiple viruses with a single small molecule. A team of 6 investigators working on interdependent projects will discover and advance small molecule inhibitors of both categories.

这个转化研究中心的目标是开发小分子抑制剂 将病毒进入并测试其在疾病动物模型中的功效。基本的假设是 被包裹的病毒进入充满了可以开发出小分子抑制剂的治疗靶标的， 阻断受体参与，膜融合和细胞运输。大多数持牌抗病毒药 药物通常通过干扰病毒编码的酶来阻止复制周期的细胞内步骤 复制所需。少数抗病毒剂阻止了包膜的病毒进入：Maraviroc，小分子 这阻止了人类免疫缺陷病毒1的GP 120对CCR5共受体的参与； Enfuvirtide，一种结合HIVI的GP41并干扰融合的合成肽；和 amantadine/rimantidine。哪个阻止了某些流感菌株的M2离子通道，以防止 病毒核糖核蛋白片段释放到细胞中。合成进入抑制剂的稀少 与经常阻止病毒进入的抗体中和抗体的自然保护机制形成对比。 该CERTER将推进两种对病毒进入的小分子抑制的一般方法：直接靶向 病毒包膜蛋白；以及针对传染性病毒进入的细胞因子的特定靶向。定位 包膜蛋白的优势是，小分子不需要进入细胞，从而消除了 吸收和潜在的出口问题，这种抑制剂可能不太可能发生不必要的互动 带有细胞蛋白。靶向细胞蛋白提供了抑制的吸引人，但未经证实的可能性 带有一个小分子的多个病毒进入。一个由6名调查人员组成的团队 项目将发现并推进这两个类别的小分子抑制剂。