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Project 2 - Novel Therapeutics for Emerging Alphavirus

项目 2 - 新兴甲病毒的新疗法

基本信息

批准号：
10380667
负责人：
DANIEL N STREBLOW
金额：
$ 93.75万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-07 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10380667
关键词：
Acute Alphavirus Alphavirus Infections Americas Animal Model Anti-Inflammatory Agents Antiviral Agents Antiviral Therapy Arthralgia Arthritis Arthritogenic Asia Biochemical Biological Assay Biological Availability Categories Cell Culture Techniques Cell Line Chemicals Chikungunya virus Chronic Clinical Collaborations Combined Modality Therapy Computer Analysis Computer Models Crystallization Culicidae Development Disease Disease Outbreaks Drug Kinetics Drug resistance Eastern Equine Encephalomyelitis Economics Encephalitis Epidemic Europe Flavivirus Goals Health Human Immune Immune system In Vitro Infection Inflammatory Institutes Lead Life Life Cycle Stages Maps Molecular Target National Institute of Allergy and Infectious Disease Neurologic Nucleosides Pathogenicity Pathology Persons Pharmaceutical Chemistry Pharmaceutical Preparations Phylogenetic Analysis Prodrugs Property Proteins RNA Viruses RNA-Directed RNA Polymerase Regimen Research Resistance Resolution Rivers Ross river virus Severity of illness Solubility Specificity Structure Tenosynovitis Testing Therapeutic Treatment Efficacy Vaccines Venezuelan Venezuelan Equine Encephalomyelitis Viral Viral Drug Resistance Virus Virus Replication Western Equine Encephalitis Virus Work aging population analog arthropod-borne base cell type chikungunya combat cytotoxicity disability drug development drug discovery efficacy study helicase high throughput screening improved in silico in vivo inhibitor lead optimization mortality mouse model mutant nervous system disorder novel novel therapeutic intervention novel therapeutics nucleoside analog nucleoside inhibitor pre-clinical prevent priority pathogen screening small molecule small molecule inhibitor structural biology synergism targeted treatment viral resistance

项目摘要

PROJECT SUMMARY Mosquito-transmitted alphaviruses cause outbreaks of incapacitating acute and chronic arthritis and life- threatening encephalitis. The arthritogenic alphaviruses include the re-emerging chikungunya (CHIKV), Mayaro, and Ross River viruses. Since 2004, CHIKV has infected millions of people and expanded into Europe, Asia, and Americas. As arthritis can endure for months to years after infection with an arthritogenic alphavirus, large epidemics have severe economic consequences. The encephalitic alphaviruses include Eastern, Venezuelan (VEEV), and Western equine encephalitis viruses that are endemic to the Americas and infection can lead to mortality or long-term neurological sequelae. There are currently no approved alphavirus- specific vaccines or antiviral agents. In collaboration with Southern Research, we used HTS to identify non- toxic small molecules that inhibit CHIKV and VEEV replication. Additionally, we identified chemically distinct compound classes that display broad inhibitory activity against alphaviruses, as well as other pathogenic human viruses (e.g., flaviviruses). We also mapped resistance mutants against two highly active compounds and identified the alphavirus nsP2 helicase domain and the nsP3 macrodomain as potential antiviral targets. In addition to this work, in collaboration with the Emory Institute for Drug Development, we identified novel nucleosides, which target RNA-dependent RNA polymerases, with potent antiviral activity against alphavirus infection. Thus, we have identified potent antiviral compounds against three distinct molecular targets essential for alphavirus replication. The goal of this highly interactive Project 2 of the Antiviral Drug Discovery and Development Center (AD3C) is to develop new therapeutic strategies that inhibit alphavirus replication, prevent selection for drug resistance, and reduce alphavirus disease severity. In Specific Aim 1, lead compounds will be optimized in collaboration with Core A and Core B by iterative medicinal chemistry, cell culture-based antiviral and cytotoxicity assays, and in vivo pharmacokinetic studies to improve their efficacy, selectivity, solubility, and bioavailability. In Specific Aim 2, we will work with the other AD3C Projects to define the breadth of antiviral activity and cell type specificity, molecular targets through resistance mapping and structural/computational analyses and identify synergy profiles for compounds with potent activity. In Specific Aim 3, optimized compounds will be evaluated for in vivo efficacy using well-established pre-clinical mouse models of alphavirus infection. Since therapies that target different aspects of the viral life cycle are likely to show improved efficacy and limit the development of drug resistance, combination therapies also will be tested. Last of all, since alphavirus-induced disease includes inflammatory immune pathology, we will evaluate the therapeutic potential of combining antiviral therapy with anti-inflammatory regimens. This work will promote the development of new antiviral therapeutic strategies that have the potential to improve human health.

项目总结