Novel broad spectrum inhibitors of filovirus infection

 描述（由申请方提供）：丝状病毒与埃博拉病毒一样，是A类传染性病原体，可导致发病迅速和死亡率高的疾病。到目前为止，没有批准的疫苗或药物治疗可用于任何丝状病毒。因此，所有工作都需要最高级别的生物隔离。这阻碍了人们了解它们不寻常的感染机制和开发治疗方法的努力。开发有用疗法的主要障碍是丝状病毒超家族中所见的高水平的基因组序列多样性。这意味着疫苗可能只能保护有限数量的病毒分离株。然而，丝状病毒具有进入细胞机制的共同特征，因此，干扰进入步骤的药物很有可能广泛抑制许多病毒分离株。在这个项目中，我们 利用我们从MLPCN化学库中筛选350，000种化合物的结果。这项工作是与NCATS的Simeonov博士团队合作完成的。在筛选之后，我们发现75%的针对野生型马尔堡病毒的命中也抑制扎伊尔埃博拉病毒的感染。这意味着广谱抗丝状病毒药物是可能的。我们还发现了5种不同类型的化学支架具有活性。在拟议的项目中，我们将检查每组中的两种化合物，以：1）确定每种化合物是否对来自每个主要病毒家族的代表性埃博拉病毒具有活性，2）确定化合物是否保护作为病毒感染相关靶标的人类原代细胞类型，3）确定细胞进入步骤的病毒感染抑制机制。这项工作利用了我们在理解丝状病毒进入机制方面的专业知识，并将扩大我们与NCATS团队的合作。这项工作将通过NCATS的临床化学和动物试验促进未来开发的最佳候选化合物类别，以创造一种有用的广谱抗丝状病毒药物疗法。

 DESCRIPTION (provided by applicant): Filoviruses, like Ebolavirus, are category A infectious agents that cause disease with rapid onset and high mortality. To date, no approved vaccine or drug therapy is available for any filovirus. Therefore, all work requires the highest level of biological containment. This has hampered efforts to understand their unusual infection mechanism and develop a therapy. The main barrier against development of a useful therapy is the high level of genome sequence diversity seen in the filovirus superfamily. This means that a vaccine will probably only protect against a limited number of virus isolates. However, the filoviruses share common features of entry mechanism into cells and so, a drug that interferes with the entry step has a high chance of broadly inhibiting many virus isolates. In this project we take advantage of the outcome of our screening of 350,000 compounds from the MLPCN chemical library. The work was done in collaboration with Dr. Simeonov's team at NCATS. Following up from the screen, we found that 75% of hits against wild type Marburgvirus also inhibit infection by Zaire Ebolavirus. This means that a broad-spectrum anti-filovirus drug is possible. We also found 5 distinct classes of chemical scaffold were active. In the proposed project we will examine two compounds from each group to: 1) determine if each is active against representative Ebolaviruses from each of the major virus families, 2) determine if compounds protect human primary cell types that are relevant targets of virus infection 3) determine the mechanism of virus infection inhibition for steps of cell entry. This work draws upon our expertise in understanding filovirus entry mechanism and will extend our collaboration with the NCATS team. The work will promote the best candidate class of compounds for future development through clinical chemistry at NCATS and animal testing toward creating a useful broad-spectrum anti-filovirus drug therapy.