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）：迄今为止，埃博拉维病毒是类别的。在铁病毒超家族中看到的Aseful the基因组多样性水平。分离物。利用我们从MLPCN化学库中筛选350,000张的结果。 Zaire Ebolavirus。家族，2）确定与病毒感染相关靶标的人类原始细胞类型3）确定病毒感染的机制在细胞进入的步骤中吸引了了解FILOVIRUS的u ur专业知识，并将扩展我们与NCATS团队的合作。通过临床创建和动物测试creard的化合物用于未来摄取的化合物。

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：
10.1016/j.antiviral.2018.10.025
发表时间：
2018
期刊：
Antiviral research
影响因子：
7.6
作者：
Sakurai,Yasuteru;Sakakibara,Norikazu;Toyama,Masaaki;Baba,Masanori;Davey,RobertA
通讯作者：
Davey,RobertA