Development and validation of antivirals against Flaviviruses

黄病毒抗病毒药物的开发和验证

基本信息

批准号：
10514328
负责人：
Sara Cherry
金额：
$ 489.76万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-16 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10514328
关键词：
2019-nCoV Animal Model Animals Antiviral Agents Arboviruses Binding Biochemical Biological Assay Biological Availability Blood Vessels Cells Clinical Complement Complex Cytoplasm Dengue Development Disease Distant Ebola virus Encephalitis Endoplasmic Reticulum Endothelial Cells Evaluation Extravasation Family Flavivirus Flavivirus Infections Formulation Goals Hand Hepatitis C virus In Vitro Infection Japanese Encephalitis Laboratories Lead Libraries Liver Failure Medicine Modeling Natural Immunity Neuraxis Nucleosides Oral Pathogenesis Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Preclinical Testing Proteins RNA Viruses RNA replication RNA-Directed RNA Polymerase Resistance Small RNA Structure Syndrome Testing Therapeutic Validation Viral Viral Hemorrhagic Fevers Viral Proteins Virus Virus Replication West Nile virus ZIKA Zika Virus antiviral nucleoside analog base cell type drug development efficacy study emerging pathogen experience extracellular high throughput screening in vivo inhibitor innovation lead optimization novel novel therapeutics nucleoside analog pandemic preparedness prevent programs scaffold screening small molecule therapeutic development vaccine access

项目摘要

SUMMARY Flaviviruses cause hundreds of millions of infections annually and a range of clinical syndromes including hemorrhagic fever, encephalitis, liver failure, and congenital disease. Currently, and despite extensive screening campaigns by academic and pharmaceutical laboratories, there are no specific therapeutics against these viruses and a paucity of available vaccines. Our goal is to use innovative screening assays and novel viral protein targets to develop combinations of orally-formulated direct acting antivirals that can treat existing and emerging flaviviruses. We will develop antivirals against three essential proteins in flaviviruses. First, given that nucleoside analogs are an important class of antivirals we will develop orally bioavailable pan-antiflaviviral nucleoside analogs. We have in hand two scaffolds we are developing and will screen libraries of nucleosides for new scaffolds. As nucleosides can be broadly active, we will test the most active nucleosides against additional RNA viruses focusing on emerging viruses (e.g., SARS-CoV-2, EBOV, LASV and SFTSV) that are in our CAMPP consortium. Since flaviviruses are small RNA viruses and encode few proteins, we will develop antivirals against two of these essential protens with no known enzymatic activity: NS4A and NS1. Recently, clinically approved antiviral against the distantly related hepatitis C virus NS5B blocks infection of this non-enzymatic target. We have identified an inhibitor of ZIKV NS4A, an essential non-enzymatic viral protein, as a possible antiviral drug. As part of our program, we will use medicinal chemistry and SAR to optimize and broaden its activity against additional flaviviruses. NS1 serves a scaffold for replication complexes in the cytoplasm at the endoplasmic reticulum and also functions extracellularly to promote vascular leakage and central nervous system invasion by binding to endothelial cells and antagonizing innate immunity. We will use biochemical assays to identify drugs that bind flavivirus NS1 and then screen them for blockade of its intracellular and/or extracellular functions. Drugs that can block the functional activity of NS1 may impact viral replication and steps in pathogenesis. For those inhibitors against NS5, NS4A or NS1 that show optimal bioavailability and efficacy profiles, with in vivo levels that at several fold above their cellular EC90 values, we will advance into animal models of flavivirus infection. In addition, we will determine the barrier to resistance, test combinations of inhibitors first in vitro and ultimately in vivo to increase potency and prevent the emergence of resistance.

概括黄病毒每年引起数亿例感染和一系列临床综合征，包括出血热、脑炎、肝衰竭和先天性疾病。目前，尽管进行了广泛的筛查学术界和制药实验室开展的活动，目前还没有针对这些疾病的具体治疗方法病毒和可用疫苗的匮乏。我们的目标是使用创新的筛选方法和新型病毒蛋白目标是开发口服直接作用抗病毒药物的组合，以治疗现有和新出现的病毒黄病毒。我们将开发针对黄病毒中三种必需蛋白的抗病毒药物。首先，考虑到核苷类似物是一类重要的抗病毒药物，我们将开发口服生物可利用的泛抗黄病毒核苷类似物。我们手头有两个正在开发的支架，将筛选核苷库以寻找新的脚手架。由于核苷具有广泛的活性，我们将针对其他 RNA 测试最活跃的核苷病毒重点关注我们 CAMPP 中的新兴病毒（例如 SARS-CoV-2、EBOV、LASV 和 SFTSV）财团。由于黄病毒是小RNA病毒，编码很少的蛋白质，因此我们将开发抗病毒药物其中两种没有已知酶活性的必需蛋白质：NS4A 和 NS1。近日，临床获批 NS5B 是针对远亲丙型肝炎病毒的抗病毒药物，可阻断这种非酶靶点的感染。我们已确定 ZIKV NS4A（一种必需的非酶病毒蛋白）的抑制剂可作为一种可能的抗病毒药物。作为我们计划的一部分，我们将利用药物化学和 SAR 来优化和扩大其针对其他黄病毒。 NS1 充当细胞质内质复制复合物的支架网织和细胞外功能促进血管渗漏和中枢神经系统侵袭与内皮细胞结合并拮抗先天免疫。我们将使用生化检测来鉴定药物结合黄病毒 NS1，然后筛选它们以阻断其细胞内和/或细胞外功能。药品可以阻断 NS1 功能活性的药物可能会影响病毒复制和发病机制步骤。对于那些 NS5、NS4A 或 NS1 抑制剂在体内水平上表现出最佳的生物利用度和功效特征在比其细胞 EC90 值高出几倍的情况下，我们将进入黄病毒感染的动物模型。在此外，我们将确定耐药性屏障，首先在体外测试抑制剂组合，并最终在体内测试增加体内药效并防止耐药性的出现。