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Identification of Small Molecular Inhibitors of Rift Valley Fever Virus Replication

裂谷热病毒复制小分子抑制剂的鉴定

基本信息

批准号：
10250003
负责人：
Wenjun Ma
金额：
$ 18.24万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-08 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10250003
关键词：
Acute Affect Africa African Animals Antiviral Agents Biological Assay Blood - brain barrier anatomy Brain Bypass Cattle Cells Chemicals Collection Country Development Disease Disease Outbreaks Dose Encephalitis Evaluation Fever Goals Goat Health Hemorrhage Hepatitis Human In Vitro Inbred BALB C Mice Infection Kansas Knockout Mice Knowledge Laboratories Libraries Mitoxantrone Mus Pharmaceutical Preparations Polymerase Public Health Renilla Renilla Luciferases Research Research Activity Retinitis Ribavirin Rift Valley Fever Rift Valley fever virus STAT1 gene Sheep Structure Syndrome Testing Therapeutic United States National Institutes of Health Universities Vaccines Virulent Virus Virus Diseases Virus Inhibitors Virus Replication Work Zoonoses abortion base biocontainment facility biosafety level 2 facility cytotoxicity design detection assay drug candidate high throughput screening in vivo inhibitor/antagonist insight juvenile animal mortality mosquito-borne mouse model novel novel therapeutics screening small molecular inhibitor small molecule small molecule libraries

项目摘要

Project Summary Rift Valley fever caused by Rift Valley fever virus (RVFV) is an acute, mosquito-borne, fever-causing zoonotic disease that affects both humans and animals. Large Rift Valley fever outbreaks have occurred throughout Africa and more recently in the Arabian Peninsula. Because RVFV is no longer restricted to African countries, it has raised concerns that the disease could spread worldwide. The RVFV is a select agent that requires high biocontainment facilities. This limitation has hampered the development of RVFV antivirals and vaccines. Despite the significant impact of the disease to the economy and public health, there are no fully licensed vaccine and antivirals available in the US for human and animal use. It is urgent to identify and develop effective inhibitors against RVFV to treat exposed and infected humans and animals. Dr. Ma’s group has developed a cell-based screening assay based on the RVFV MP12 vaccine strain that expresses Renilla Luciferase using Renilla as readout to identify RVFV inhibitors, and established a STAT1-KO mouse model susceptible to infection with MP12 vaccine strain that can be used in a BSL-2 facility. Furthermore, they have screened 727 compounds from the NIH collections of which two candidates including 6-azauridine and mitoxantrone inhibited replication of MP12. They hypothesize that effective inhibitors against RVFV can be identified by screening large compound collections and by further optimization of their structures and activities, and the mechanisms of inhibitory effects of identified candidates can be determined. Thus, they plan to use the developed high-throughput assay to identify inhibitors against RVFV, evaluate their efficacy in vitro and in mice, and understand the underlying mechanisms of inhibitory effects of identified candidates through two specific aims in this R21 proposal. In specific aim 1, the libraries assembled by the University of Kansas High Throughput Screening Laboratory that contain approximately 26,000 chemical compounds will be screened. The 26,000 compounds are predicted to cross the blood-brain barrier. Hits from the library will help overcome the challenge for RVFV antivirals to reach the brain through the blood-brain barrier to protect encephalitis. Primary hits will be confirmed by in vitro and in vivo assays. In specific aim 2, 6-azauridine and mitoxantrone as well as others identified in Aim 1 will be evaluated in vitro and in the BALB/c mice using virulent RVFV. To understand the underlying mechanisms of their inhibitory effects, whether the compounds block virus entry, inhibit virus replication and polymerase activity will be investigated using different designed assays. The results of this study could identify novel effective inhibitors against RVFV and understand the underlying mechanisms of their inhibitory effects, and offer novel insights toward the design of novel antiviral drugs against this zoonotic disease that will benefit both human and animal health.

项目总结