Small molecule inhibitors of enveloped virus entry

该转化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功效。潜在的假设是， 包膜病毒的进入充满了可以开发小分子抑制剂的治疗靶点， 阻断受体结合、膜融合和细胞运输。大多数类别的许可的抗病毒药物 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 需要复制。少数抗病毒剂阻止包膜病毒进入：马拉韦罗，一种小分子 阻断CCR 5辅助受体与人类免疫缺陷病毒-1的gp 120的结合; 恩夫韦肽，一种结合HIVI gp 41并干扰融合的合成肽;和 金刚烷胺/金刚乙胺。阻断某些甲型流感病毒株的M2离子通道， 病毒核糖核蛋白片段释放到细胞中。合成进入抑制剂的缺乏 与中和抗体的天然保护机制形成对比，中和抗体经常阻止病毒进入。 该CETR将推进两种一般的小分子抑制病毒进入的方法：直接靶向 病毒包膜蛋白;以及感染性病毒进入所必需的细胞因子的特异性靶向。靶向 包膜蛋白具有小分子不需要进入细胞的优点，从而消除了 吸收和潜在的出口问题，这样的抑制剂可能不太可能有不必要的相互作用 细胞蛋白质。靶向细胞蛋白质提供了有吸引力的，但未经证实的可能性，以抑制肿瘤细胞的增殖。 多个病毒通过单个小分子进入。一个由6名调查员组成的小组， 项目将发现和推进这两类小分子抑制剂。

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.