Receptor-directed small-molecule inhibitors of New World hemorrhagic fever mammarenavirus entry

新世界出血热乳腺病毒入侵的受体定向小分子抑制剂

基本信息

批准号：
10358610
负责人：
Brian B. Gowen
金额：
$ 20.15万
依托单位：
UTAH STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-24 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10358610
关键词：
Advanced Development Americas Animals Antiviral Agents Antiviral Therapy Apical Binding Binding Proteins Biological Availability Bolivian Hemorrhagic Fever Virus Cell Culture Techniques Cells Chemicals Complex Disease Docking Dose Drug Kinetics Drug resistance Evaluation Foundations Frequencies GTPBP1 gene Glycoproteins Goals Hemochromatosis Histopathology Human In Vitro Infection Investigational Drugs Junin virus Knock-in Mouse Lead Life Ligands Maximum Tolerated Dose Measures Metabolic Metabolism Modeling Modification Mus National Security Oral Pathogenicity Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Plasma Proteins Population Property Proteins Public Health Records Research Research Project Grants Risk Rodent Science Severity of illness Site Solubility Structure Structure-Activity Relationship Syndrome TFRC gene Testing Therapeutic Therapeutic Agents Transferrin Vaccines Viral Viral Hemorrhagic Fevers Viral Load result Virus Zoonoses absorption analog antiviral drug development aptamer base cytotoxicity design druggable target efficacy study experimental study illness length improved indexing innovation lead candidate lead optimization molecular modeling mouse model nanomolar nonhuman primate novel pharmacophore preclinical development receptor scaffold small molecule inhibitor small molecule therapeutics success survival outcome therapeutic candidate therapeutic target transmission process treatment duration virology virtual screening virus envelope

项目摘要

PROJECT SUMMARY Mammarenaviruses are endemic in rodent populations worldwide and zoonotic transmission can lead to severe life-threatening hemorrhagic fever. In the Americas, five mammarenavirus species, including Junín and Machupo viruses (JUNV and MACV, respectively), cause viral hemorrhagic fever. In the absence of FDA-licensed antiviral therapies or vaccines, these viruses pose a significant public health concern and threaten national security. The pathogenic New World mammarenaviruses (NWMs) utilize the human transferrin receptor 1 (hTfR1) for entry into human cells. The GP1 subunit of the virus envelope glycoprotein binds to the apical domain of hTfR1, a region that is not involved in the binding to the major hTfR1 ligands. This interaction between GP1 and hTfR1 therefore represents a potential therapeutic target for broad inhibition of NWM infection. Based on the structure of the MACV envelope glycoprotein GP1 subunit in complex with hTfR1, we identified a novel druggable site in the apical domain of hTfR1. A docking-based virtual screening campaign identified 28 hits that were subsequently characterized to determine antiviral activity against JUNV infection in cell culture. Based on this assessment, we selected two chemically distinct molecules displaying strong activity against JUNV for further consideration. We hypothesize that targeting the apical domain pocket of hTfR1 that interacts with viral GP1 will broadly inhibit infection by all known pathogenic NWMs and thereby protect mice expressing hTfR1 from lethal disease associated with JUNV infection. To explore this hypothesis, we will pursue the following specific aims. Aim 1. Identify potent and broadly active compounds targeting the druggable hTfR1 apical domain site that interacts with NWM GP1. The two distinct chemical scaffolds identified in our preliminary studies will serve as the foundation for the design of analogs to define structure-activity relationships (SARs) important for broad antiviral activity. We will implement an iterative campaign involving molecular modeling, medicinal chemistry and in vitro antiviral testing against native JUNV and pseudotyped viruses displaying the envelope glycoprotein of NWMs. Our strategy will include optimization for drug-like properties. Aim 2. Evaluate pharmacokinetics (PK) and efficacy of optimized lead candidates in hTfR1 mice. Two optimized compounds from each chemical scaffold will be chosen for evaluation in animals based on their in vitro potency, selectivity, breadth of inhibition and drug-like properties. We will assess oral bioavailability, determine the maximum tolerated dose and establish PK profiles for the lead candidates in mice. Results from these studies will guide decisions regarding dosing levels and the frequency and duration of treatment in subsequent efficacy studies in a validated hTfR1 mouse model of lethal JUNV infection. In addition to improved survival outcome in JUNV-challenged hTfR1 mice, we will measure the impact of treatments on viral loads, histopathology, and disease severity and duration. Our long-term goal is to develop a novel host-directed small-molecule therapeutic agent that could be deployed to treat NWM hemorrhagic fevers.

项目概要乳房病毒在全世界啮齿类动物中流行，人畜共患传播可导致严重的疾病在美洲，有五种哺乳动物病毒，包括胡宁病毒和马丘波病毒。在没有 FDA 许可的抗病毒药物的情况下，病毒（分别为 JUNV 和 MACV）会引起病毒性出血热。疗法或疫苗，这些病毒构成重大公共卫生问题并威胁国家安全。致病性新世界乳房病毒 (NWM) 利用人转铁蛋白受体 1 (hTfR1) 进入病毒包膜糖蛋白的 GP1 亚基与 hTfR1 的顶端结构域结合。不参与与主要 hTfR1 配体结合的区域 GP1 和 hTfR1 之间的相互作用。因此，基于该结构，它代表了广泛抑制 NWM 感染的潜在治疗靶点。通过对与 hTfR1 复合的 MACV 包膜糖蛋白 GP1 亚基的研究，我们发现了一个新的可成药位点基于对接的虚拟筛选活动确定了 28 个 hTfR1 的顶端域。随后进行表征以确定细胞培养物中针对 JUNV 感染的抗病毒活性。评估中，我们选择了两种化学性质不同的分子，对 JUNV 表现出强大的活性，以进一步研究我们考虑了针对与病毒 GP1 相互作用的 hTfR1 顶端结构域口袋。将广泛抑制所有已知致病性 NWM 的感染，从而保护表达 hTfR1 的小鼠免受感染与 JUNV 感染相关的致死性疾病为了探讨这一假设，我们将进行以下具体研究。目标 1. 鉴定针对可药物化 hTfR1 顶端结构域的有效且具有广泛活性的化合物。我们初步研究中确定的两种不同的化学支架将与 NWM GP1 相互作用。作为设计类似物的基础，以定义重要的结构-活性关系（SAR）我们将实施一项涉及分子建模、药物的迭代活动。针对天然 JUNV 和展示包膜的假型病毒进行化学和体外抗病毒测试我们的策略将包括优化药物样特性。目标 2. 评估。优化的先导候选药物在 hTfR1 小鼠中的药代动力学 (PK) 和功效。将根据其体外效力选择来自每种化学支架的化合物用于动物评估，我们将评估口服生物利用度，确定选择性、抑制范围和药物样特性。这些研究的结果是最大耐受剂量并建立主要候选药物的 PK 曲线。将指导有关剂量水平以及治疗频率和持续时间的后续疗效决策在经过验证的致死性 JUNV 感染 hTfR1 小鼠模型中进行的研究除了改善患者的生存结果外。 JUNV 攻击的 hTfR1 小鼠，我们将测量治疗对病毒载量、组织病理学和我们的长期目标是开发一种新型的针对宿主的小分子治疗方法。可用于治疗 NWM 出血热的药物。