Antiviral Lead Identification to Treat Filovirus Infections

治疗丝状病毒感染的抗病毒先导药物鉴定

基本信息

批准号：
9765787
负责人：
ROBERT A DAVEY
金额：
$ 63.96万
依托单位：
PURDUE UNIVERSITY
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：
2019-08-12 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9765787
关键词：
Address Affect Animal Disease Models Animal Model Antiviral Agents Antiviral Therapy Binding Biochemical Biochemistry Biological Assay Biological Availability Biomedical Research Boston Category A pathogen Cell model Cells Cellular Assay Chemicals Chemistry Data Dendritic Cells Development Disease Dose Drug Kinetics Drug Targeting Drug effect disorder Ebola virus Endosomes Filoviridae Infections Filovirus Formulation Frankfurt-Marburg Syndrome Virus Funding Mechanisms Goals Hepatocyte Human In Vitro Infection Integration Host Factors Intervention Ion Channel Lactones Lead Measures Metabolic Modeling Molecular Mus National Institute of Allergy and Infectious Disease Natural Products Oral Outcome Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pharmaceutical Technology Pharmacologic Substance Pharmacology Phenotype Plasma Population Primary Infection Process Property Pump Relative Risks Research Research Institute Research Personnel Retroviridae Risk Safety Selection Criteria Series Site Structure Testing Texas Therapeutic Tissues Toxic effect Toxicology Translating Translations Universities Validation Vesicle Viral Virus Virus Replication analog anti-viral efficacy base biosafety level 4 facility design drug development efficacy study efficacy testing improved in vitro testing in vivo in vivo Model inhibitor/antagonist insight late endosome lead candidate macrophage member mouse model nonhuman primate novel strategies novel therapeutics pathogenic virus pre-clinical prevent safety testing small molecule vacuolar H+-ATPase

项目摘要

A research team from Purdue University and Texas Biomedical Research Institute is in pursuit of important new approaches to validate the host V-ATPase. The project goal to define antiviral drug leads for diseases caused by Ebola and Marburg filoviruses. Many viral pathogens bind to specific factors of host cells to penetrate the plasma member inside vesicles called endosomes. However, entry of the virus to the host cells requires escape from these vesicles. A majority of these viruses utilize the low pH of late endosomes to trigger the final steps in viral entry. Since the acidification of endosomes depends on vacuolar H(+)-ATPases (V-ATPases), inhibiting this pump interferes with entry of a wide range of viruses. Thus, the host V-ATPase represents a truly broad-spectrum target for antiviral drugs. While feasible, there are challenges for developing antiviral drugs that targets host factors like V-ATPase because of the potential risk of toxicity to non-infected cells and tissues. The approach used in this project directly addresses this challenge which will apply discovery and pharmaceutical technologies to achieve selectivity of drug action. The project team brings significant expertise to the challenges for discovery and development of host-targeted antiviral therapeutics. Efforts will integrate chemistry and biochemistry of natural-product V-ATPase inhibitors, viral-host entry pathways, Ebola and Marburg animal disease models in BSL4 facility, in vitro and in vivo ADME-pharmacokinetics, and toxicology. Currently, there is a lack of suitable in vivo chemical probes available to test safety and efficacy of pharmaceutical interventions targeting V-ATPase. The objectives for this five-year project are to: a) qualify a class of selective chemical inhibitors for V-ATPase suitable for in vivo antiviral efficacy testing, and b) identify a new drug lead candidate targeting V-ATPase function during the viral entry process for Ebola and Marburg filoviruses. These complementary objectives will impact the prospects and precise strategy for developing antiviral therapies to treat unmet needs.

来自普渡大学和德克萨斯生物医学研究所的一个研究小组正在寻求重要的新方法来验证宿主 V-ATP 酶。该项目的目标是确定针对埃博拉和马尔堡丝状病毒引起的疾病的抗病毒药物先导化合物。许多病毒病原体与宿主细胞的特定因子结合，穿透称为内体的囊泡内的血浆成员。然而，病毒进入宿主细胞需要逃离这些囊泡。大多数这些病毒利用晚期内涵体的低pH值来触发病毒进入的最后步骤。由于内体的酸化依赖于液泡 H(+)-ATP 酶（V-ATP 酶），因此抑制该泵会干扰多种病毒的进入。因此，宿主V-ATP酶代表了抗病毒药物的真正广谱靶标。虽然可行，但开发针对 V-ATP 酶等宿主因子的抗病毒药物仍面临挑战，因为对未感染的细胞和组织存在潜在的毒性风险。该项目使用的方法直接解决了这一挑战，该方法将应用发现和制药技术来实现药物作用的选择性。该项目团队带来了重要的专业知识，以应对发现和开发针对宿主的抗病毒疗法的挑战。我们将努力整合天然产物 V-ATP 酶抑制剂的化学和生物化学、病毒宿主进入途径、BSL4 设施中的埃博拉和马尔堡动物疾病模型、体外和体内 ADME 药代动力学以及毒理学。目前，缺乏合适的体内化学探针来测试针对 V-ATP 酶的药物干预的安全性和有效性。这个为期五年的项目的目标是：a) 鉴定一类适用于体内抗病毒功效测试的 V-ATP 酶选择性化学抑制剂，以及 b) 确定一种在病毒进入过程中针对 V-ATP 酶功能的新药物先导候选药物埃博拉和马尔堡丝状病毒的处理过程。这些互补的目标将影响开发抗病毒疗法来治疗未满足的需求的前景和精确策略。