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.

概括 拉沙病毒 (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）对公众健康构成威胁， 由于总体缺乏有效的抗病毒疗法来对抗这些感染，情况进一步恶化。尽管 它们不同的基因组组织和生物学，乳腺病毒 (LASV)、班阳病毒 (SFTSV) 和 丝状病毒 (EBOV) 具有相似的 RNA 生物合成策略，其中病毒核蛋白包裹着 病毒基因组 RNA 形成核衣壳 (NC)，作为 RNA 合成和复制的模板 和转录，由相关的病毒RNA依赖性RNA聚合酶（RdRp，L蛋白）介导 病毒核糖核蛋白复合物（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 vRNP 病毒成分的抗病毒药物。为此，我们对 采用 HTS 进行基于细胞和生化的检测，以鉴定病毒 RdRp 活性和 NC 的抑制剂 LASV、SFTSV 和 EBOV 的形成，以及 L 蛋白核酸内切酶和帽结合活性 LASV 和 SFTSV 抢帽子介导的转录所需。初始命中，由 HTS 使用目标识别 基于特定细胞或生化检测的检测将得到验证，并在目标确认后进行 共同管道涉及正式命中评估 (FHA)、早期和晚期命中引导 (H2L) 步骤以及引导 优化（leadOP），这将促进本项目范围之外的 IND 支持步骤。这项研究 该项目建立在与 CAMPP 核心的强大协同作用之上。药物化学和结构与 Modeling Cores 将使用基于结构的药物设计来合成具有改进的化合物衍生物 生物和药代动力学特性，而感染核心动物模型将能够在体内 选定线索的功效研究。