Development and validation of antivirals against hemorrhagic fever viruses of pandemic concern

针对大流行病的出血热病毒的抗病毒药物的开发和验证

• 批准号: 10514329
• 负责人: Juan C. de la Torre
• 金额: $ 686.93万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 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/10514329
• 关键词: Address; Animal Model; Antiviral Agents; Binding; Biochemical; Biological; Biological Assay; Biology; C-terminal; Cell Culture Techniques; Cells; Chemicals; Chemistry; Collection; Complex; Development; Dose; Drug Design; Drug Kinetics; Ebola virus; Energy Transfer; Filovirus; Fluorescence Polarization; Formulation; Funding Agency; Gel; Genetic Transcription; Genome; Goals; Infection; Lassa virus; Lead; Libraries; Mediating; Medicine; Modification; Molecular Bank; Mus; N-terminal; Nucleocapsid; Nucleoproteins; Pharmaceutical Chemistry; Pharmacologic Substance; Polymerase; Process; Property; Proteins; Proteomics; Public Health; RNA; RNA chemical synthesis; RNA-Directed RNA Polymerase; Research; Research Project Grants; Ribonucleoproteins; Secondary to; Severe Fever with Thrombocytopenia Syndrome Virus; Structural Models; Structure; Testing; Toxic effect; Toxicology; Transcription Initiation; Triage; United States National Institutes of Health; Validation; Viral; Viral Genome; Viral Physiology; Virus; Virus Diseases; Virus Inhibitors; Virus Replication; Zoonoses; base; combat; design; efficacy study; endonuclease; hemorrhagic fever virus; improved; in vivo; inhibitor; lead optimization; novel; nucleoside analog; pandemic disease; pandemic preparedness; pharmacokinetics and pharmacodynamics; repository; response; screening; small molecule libraries; synergism; viral RNA

SUMMARY Lassa virus (LASV), severe fever with thrombocytopenia syndrome virus (SFTSV), and Ebola virus (EBOV) are hemorrhagic fever causing viruses (HFV) of pandemic concern that pose a threat to public health, a situation exacerbated by an overall lack of effective antiviral therapeutics to combat these infections. Despite their different genome organization and biology, mammarenaviruses (LASV), banyangviruses (SFTSV) and filoviruses (EBOV) share a similar RNA biosynthetic strategy where the viral nucleoprotein encapsidates the viral genome RNA to form a nucleocapsid (NC) that serves as template for RNA synthesis, both replication and transcription, mediated by the associated viral RNA dependent RNA polymerase (RdRp, L protein) in the context of a viral ribonucleoprotein complex (vRNP). The central goal of this Project 6 of CAMPP is to discover and develop antivirals targeting viral components of LASV, SFTSV and EBOV vRNPs. For this, we have on place cell-based and biochemical assays amenable to HTS to identify inhibitors of viral RdRp activity and NC formation for LASV, SFTSV and EBOV, as well as the L protein endonuclease and cap-binding activities required for LASV and SFTSV cap-snatching mediated transcription. Initial hits, identified by HTS using target- specific cell based or biochemical assays, will be validated and, following target confirmation, subjected to a common pipeline involving formal hit assessment (FHA), early and late hit-to-lead (H2L) steps, and lead optimization (leadOP), which will facilitate IND-enabling steps outside the scope of this project. This research project builds on the strong synergy with the CAMPP Cores. The Medicinal Chemistry and Structural and Modeling Cores will use structure-based drug design to synthesize compound derivatives with improved biological and pharmacokinetic properties, whereas the Animal Models of Infection Core will enable in vivo efficacy studies of selected leads.

摘要 拉萨病毒(LASV)、严重发热伴血小板减少综合征病毒(SFTSV)和埃博拉病毒(EBOV) 引起大流行的出血热病毒(HFV)是否对公众健康构成威胁 由于总体上缺乏有效的抗病毒疗法来抗击这些感染，这种情况进一步恶化。尽管 它们不同的基因组组织和生物学，哺乳动物病毒(LASV)，榕树病毒(SFTSV)和 丝状病毒(EBOV)共享类似的RNA生物合成策略，即病毒核蛋白包裹 病毒基因组RNA形成核衣壳(NC)，作为RNA合成的模板，两者复制 和转录，由相关的病毒RNA依赖的RNA聚合酶(RdRp，L蛋白)在 病毒核糖核蛋白复合体(VRNP)的背景。CAMPP项目6的中心目标是发现 并开发针对LASV、SFTSV和EBOV vRNPs病毒组件的抗病毒药物。为此，我们有 放置适合HTS的细胞和生化分析，以确定病毒RdRp活性和NC的抑制物 LASV、SFTSV和EBOV的形成以及L蛋白内切酶和帽结合活性 LASV和SFTSV帽子抓取介导的转录所必需的。最初的命中，HTS使用目标识别- 基于特定细胞的或生化分析将得到验证，并在目标确认后，接受 通用渠道，包括正式命中评估(FHA)、早期和晚期命中到领先(H2 L)步骤，以及领先 优化(LeadOP)，这将促进本项目范围之外的启用IND的步骤。这项研究 该项目建立在与CAMPP核心的强大协同作用之上。药物化学与结构与化学 模型核将使用基于结构的药物设计来合成具有改进的 生物学和药代动力学特性，而感染的动物模型核心将使在体内 精选线索的功效研究。