Small molecule inhibitors of enveloped virus entry

这个翻译研究卓越中心的目标是开发小分子抑制剂 包膜病毒进入并在疾病动物模型中测试其疗效。基本的假设是 包膜病毒进入充满了治疗靶点，可以针对这些靶点开发小分子抑制剂， 阻断受体结合、膜融合和细胞运输。大多数类别的许可抗病毒药物 药物通常通过干扰病毒编码的酶来阻断复制周期的细胞内步骤 复制所需的。几种抗病毒药物可以阻止包膜病毒的进入：马拉韦罗，一种小分子 阻断人类免疫缺陷病毒-1的GP 120与CCR5共受体的结合； 恩福韦肽，一种与HiVi的gp41结合并干扰融合的合成肽；以及 金刚烷胺/金刚乙胺。它阻断某些甲型流感病毒株的M2离子通道，以防止 将病毒核糖核蛋白片段释放到细胞内。缺乏人工合成的进入抑制物 与中和抗体的自然保护机制形成对比，中和抗体经常阻止病毒进入。 这项CETR将提出两种抑制小分子病毒进入的一般方法：直接靶向 病毒包膜蛋白；以及针对传染性病毒进入所需的细胞因子的特定靶点。瞄准 包膜蛋白的优点是小分子不需要进入细胞，从而消除了 吸收和潜在的出口担忧，这种抑制剂可能不太可能产生不必要的相互作用 与细胞蛋白质结合。靶向细胞蛋白提供了一种诱人的、尽管未经证实的可能性来抑制 用单个小分子进入多个病毒。一个由6名调查人员组成的团队致力于相互依赖 项目将发现并推动这两类小分子抑制剂的发展。

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.