Novel broad spectrum inhibitors of filovirus infection

 描述(申请人提供)：丝状病毒，与埃博拉病毒一样，是引起疾病的A类传染病病原体，起病快，死亡率高。到目前为止，还没有针对任何丝状病毒的批准的疫苗或药物疗法。因此，所有工作都需要最高水平的生物遏制。这阻碍了了解它们不同寻常的感染机制和开发治疗方法的努力。阻碍开发有效疗法的主要障碍是丝状病毒超家族中看到的高水平的基因组序列多样性。这意味着疫苗可能只对有限数量的病毒分离株有保护作用。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有很高的机会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。这项工作是与西蒙诺夫博士在NCATS的团队合作完成的。从屏幕上跟踪，我们发现75%的针对野生型马尔堡病毒的命中率也抑制了扎伊尔埃博拉病毒的感染。这意味着一种广谱抗丝病毒药物是可能的。我们还发现5种不同类别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个化合物，以：1)确定每个化合物是否对来自每个主要病毒家族的典型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目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了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来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.