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

• 批准号: 10453443
• 负责人: ROBERT A DAVEY
• 金额: $ 63.7万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-12 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453443
• 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; Ebola; Ebola virus; Endosomes; Filoviridae Infections; Filovirus; Formulation; Funding Mechanisms; Goals; Hepatocyte; Human; In Vitro; Infection; Integration Host Factors; Intervention; Ion Channel; Lactones; Lead; Marburgvirus; 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; Testing; Texas; Therapeutic; Tissues; Toxic effect; Toxicology; Translating; Translations; Universities; Validation; Vesicle; Viral; Virus; Virus Replication; analog; antagonist; anti-viral efficacy; antiviral drug development; base; biosafety level 4 facility; design; drug action; efficacy study; efficacy testing; improved; in vitro testing; in vivo; in vivo Model; inhibitor; 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; viral entry inhibitor

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由埃博拉和马尔堡丝状病毒引起的疾病的抗病毒药物先导物。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浆体成员。然而，病毒进入宿主细胞需要逃离这些囊泡。这些病毒中的大多数利用后期核内体的低pH值来触发病毒进入的最后步骤。由于内体的酸化取决于空泡H(+)- atp酶（v - atp酶），抑制这种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存在挑战，因为对未感染的细胞和组织有潜在的毒性风险。本项目中使用的方法直接解决了这一挑战，它将应用发现和制药技术来实现药物作用的选择性。项目团队为发现和开发针对宿主的抗病毒治疗带来了重要的专业知识。他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药代动力学和毒理学。目前，缺乏合适的体内化学探针来检测针对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)确定一类适合体内抗病毒功效测试的V-ATPase选择性化学抑制剂，以及b)确定一种新的候选药物，靶向埃博拉和马尔堡丝状病毒在病毒进入过程中的V-ATPase功能。这些互补的目标将影响开发抗病毒疗法以治疗未满足需求的前景和精确策略。