Novel broad spectrum inhibitors of filovirus infection

丝状病毒感染的新型广谱抑制剂

基本信息

批准号：
9131611
负责人：
ROBERT A DAVEY
金额：
$ 23.13万
依托单位：
TEXAS BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-24 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9131611
关键词：
Amino Acids Animal Model Animal Testing Antibody Response Arenavirus Biochemical Biological Assay Biological Containment Categories Cells Cessation of life Chemicals Clinical Chemistry Collaborations Containment Cytoplasm Democratic Republic of the Congo Development Disease Disease Outbreaks Drug Formulations Endothelial Cells Exanthema Extravasation Family Filovirus Frankfurt-Marburg Syndrome Virus Funding Future Genetic Glycoproteins Goals Health Hemorrhage Human Infection Infectious Agent Laboratories Lassa fever virus Lead Literature Membrane Multiple Organ Failure Nucleocapsid Outcome Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacotherapy Preclinical Drug Evaluation Principal Investigator Problem Solving Process Productivity Property Proteins Publishing Reporting Reston Robotics Shock Staging Sudan Symptoms System Techniques Test Result Testing Time Translational Research Umbilical vein Universities Vaccination Vaccine Therapy Vaccines Variant Vascular Permeabilities Viral Hemorrhagic Fevers Virion Virus Virus Diseases Virus-like particle Work adaptive immunity cell type chemical fingerprinting flu forest genome sequencing in vivo Model inhibitor/antagonist innovation interest macrophage mortality neutralizing antibody nonhuman primate novel prevent programs receptor binding scaffold screening small molecule small molecule libraries targeted treatment trafficking uptake virus infection mechanism

项目摘要

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.

描述（由申请人提供）：丝状病毒与埃博拉病毒一样，属于 A 类传染性病原体，可引起快速发病和高死亡率的疾病，迄今为止，还没有针对任何丝状病毒的批准的疫苗或药物治疗，因此，所有工作都需要最高水平。这阻碍了了解其不寻常的感染机制和开发治疗方法的主要障碍是丝状病毒超家族中发现的高水平的基因组序列多样性。只能防御有限数量的病毒分离株，但是，丝状病毒具有进入细胞的共同特征，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。利用我们与 NCATS Simeonov 博士团队合作筛选 MLPCN 化学库中的 350,000 种化合物的结果，我们发现 75% 的针对野生型马尔堡病毒的命中也具有抑制作用。扎伊尔埃博拉病毒感染，这意味着广谱抗丝状病毒药物是可能的。在拟议的项目中，我们将研究两种化合物。 1) 确定每种化合物是否对每个主要病毒家族的代表性埃博拉病毒有活性，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，通过 NCATS 的临床化学和动物测试来促进未来开发的最佳候选化合物类别。有用的广谱抗丝状病毒药物治疗。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（2）

Novel amodiaquine derivatives potently inhibit Ebola virus infection.

新型阿莫地喹衍生物可有效抑制埃博拉病毒感染。

DOI：
发表时间：
2018
期刊：
影响因子：
7.6
作者：
Sakurai, Yasuteru;Sakakibara, Norikazu;Toyama, Masaaki;Baba, Masanori;Davey, Robert A
通讯作者：
Davey, Robert A

Identification of Ellagic Acid from Plant Rhodiola rosea L. as an Anti-Ebola Virus Entry Inhibitor.

鉴定植物红景天中的鞣花酸作为抗埃博拉病毒侵入抑制剂。

DOI：
发表时间：
2018-03-27
期刊：
影响因子：
0
作者：
Cui, Qinghua;Du, Ruikun;Anantpadma, Manu;Schafer, Adam;Hou, Lin;Tian, Jingzhen;Davey, Robert A;Cheng, Han;Rong, Lijun
通讯作者：
Rong, Lijun