Antiviral Lead Identification to Treat Filovirus Infections

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找重要的新方法来验证宿主V-ATPase。该项目的目标是为埃博拉和马尔堡丝状病毒引起的疾病确定抗病毒药物的先导。许多病毒病原体与宿主细胞的特定因子结合，以穿透被称为内小体的小泡内的血浆成员。然而，病毒进入宿主细胞需要逃离这些小泡。这些病毒中的大多数利用晚期内体的低pH值来触发病毒进入的最后步骤。由于内体的酸化依赖于空泡H()-ATPase(V-ATPase)，抑制这一泵会干扰广泛的病毒进入。因此，宿主V-ATPase代表了抗病毒药物的真正广谱靶点。虽然可行，但开发针对V-ATPase等宿主因素的抗病毒药物存在挑战，因为对未感染的细胞和组织具有潜在的毒性风险。该项目中使用的方法直接应对这一挑战，它将应用发现和制药技术来实现药物作用的选择性。该项目团队为发现和开发宿主靶向抗病毒疗法带来了重要的专业知识。将努力整合天然产品V-ATPase抑制剂、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的化学和生物化学。目前，缺乏合适的体内化学探针来测试针对V-ATPase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疗效测试的V-ATPase选择性化学抑制剂，以及b)确定在埃博拉和马尔堡丝状病毒进入病毒过程中针对V-ATPase功能的新的候选药物。这些相辅相成的目标将影响开发抗病毒疗法以治疗未得到满足的需求的前景和精确战略。

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.