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Validating the Flavivirus Envelope Protein as an Antiviral Target

验证黄病毒包膜蛋白作为抗病毒靶点

基本信息

批准号：
10413666
负责人：
NATHANAEL Schiander GRAY
金额：
$ 85.19万
依托单位：
STANFORD UNIVERSITY
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：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10413666
关键词：
ADME Study Address Animal Model Antiviral Agents Automobile Driving Binding Binding Proteins Binding Sites Biochemical Biological Assay Biology Chemicals Complex Computational Biology Computer Analysis Computer Models Culicidae Dengue Infection Dengue Virus Development Disease Docking Drug Design Drug Kinetics Drug Targeting E protein Engineering Enzymes Evaluation Flavivirus Foundations Future Glucosides Goals Immune response Immunity In Vitro Infection Japanese encephalitis virus Kinetics Lead Libraries Liposomes Maximum Tolerated Dose Measures Mediating Membrane Fusion Microsomes Minority Modeling Pain interference Peptide Hydrolases Pharmaceutical Chemistry Pharmaceutical Preparations Phenotype Plasma Proteins Polymerase Property Proteins Public Health Recombinants Resistance Resistance profile Resources Serial Passage Series Serotyping Site Site-Directed Mutagenesis Solubility Structural Models Structure Therapeutic Time Viral Viral Envelope Proteins Viremia Virion Virus Virus Inhibitors West Nile virus Work X-Ray Crystallography ZIKA Zika Virus anti-viral efficacy aqueous base combat cytotoxicity design efficacy testing env Gene Products experimental study extracellular flavivirus envelope protein E high throughput screening human pathogen in silico in vivo in vivo Model in vivo evaluation inhibitor/antagonist lead optimization lead series mouse model mutant novel therapeutics particle pathogen process optimization prophylactic resistance mutation screening small molecule small molecule inhibitor structural biology viral entry inhibitor viral resistance virus envelope

项目摘要

PROJECT SUMMARY Dengue virus (DENV) and other flaviviruses are major human pathogens that cause significant disease. Transmitted by widespread mosquito species, many of these viruses spread rapidly and can have a devastating impact on public health where prior immunity does not exist. There is thus a significant need for countermeasures to combat both current and future flavivirus threats. Major limitations in current antivirals development are the relatively small number of validated antiviral targets, most of which are viral enzymes (e.g., polymerases, proteases); the low barrier to resistance when direct-acting antivirals are used as monotherapies; and the narrow spectrum activity of most of these agents (“one bug, one drug”). New classes of targets that can mediate broad-spectrum activity against related viruses and that have high barriers to resistance are particularly needed to combat emerging viruses since we generally lack sufficient time and resources to develop new drugs on a useful time scale once these viruses pose significant threats. Small molecules targeting the flavivirus envelope protein, E, have the potential to mimic the humoral immune response by engaging their target extracellularly and blocking viral entry early in the replication cycle. We have identified multiple small molecule inhibitor series that bind to the DENV envelope protein, E, and inhibit E-mediated membrane fusion during viral entry even when only a minority of copies of E on the particle are inhibitor-bound. These compounds bind in a pocket between domains I and II and inhibit West Nile, Zika, and Japanese encephalitis viruses due to at least partial conservation of this site. We recently established a target-based assay and validated its use in the identification of new inhibitors of DENV and Zika E proteins that bind in the conserved pocket and that have more drug-like properties than our original inhibitors. Building on this work, we now propose a comprehensive plan to rationally optimize small molecule inhibitors of the DENV E protein as a potential anti-viral strategy. Towards this end, we will combine modeling and structure- guided drug design with an efficient screening cascade using complementary target-based biochemical, cellular and mechanistic assays to enable efficient optimization of two chemically distinct lead series. Our primary goal in this work is to demonstrate antiviral efficacy in a murine model of DENV infection, thus laying the foundation for first-in-class direct acting antivirals to treat the growing global threat that DENV poses.

项目总结