Project 5: Pandemic Virus Helicase Inhibitors

项目5：大流行病毒解旋酶抑制剂

• 批准号: 10522814
• 负责人: Donghoon Chung
• 金额: $ 495.13万
• 依托单位: UNIVERSITY OF MINNESOTA
• 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/10522814
• 关键词: 2019-nCoV; Address; Alphavirus; Animal Model; Animals; Antiviral Agents; Binding Proteins; Biochemical; Biochemistry; Biological Assay; Biophysics; Chemicals; Chemistry; Complex; Coronavirus; DNA; Development; Dose; Drug Design; Drug resistance; Family; Flavivirus; Fluorescence; Future; Genome; Goals; Head; In Vitro; Lead; Libraries; Midwestern United States; Mus; Oral; Peptide Hydrolases; Performance; Pharmaceutical Chemistry; Pharmaceutical Preparations; Polymerase; Property; RNA Helicase; RNA Viruses; RNA chemical synthesis; Regimen; Reporting; SARS-CoV-2 antiviral; SARS-CoV-2 infection; Scheme; Sequence Homology; Series; Spices; Structure; Technology; Testing; Therapeutic; Therapeutic Index; Toxic effect; Translations; Validation; Vendor; Viral; Virus; Virus Diseases; Virus Replication; Zika Virus; analog; anti-viral efficacy; antiviral drug development; base; candidate selection; computational chemistry; drug candidate; drug development; drug discovery; efficacy study; helicase; high throughput screening; improved; in vivo; in vivo evaluation; inhibitor; interdisciplinary approach; lead optimization; lead series; novel; pandemic disease; pathogenic virus; pharmacokinetics and pharmacodynamics; preclinical study; replicase; response; screening; small molecule; structural biology; success; validation studies; viral RNA; virology

Project 5 – Pandemic Virus Helicase Inhibitors ABSTRACT The goal of this project is to develop pan-family, antiviral drug candidates targeting the viral helicase of coronavirus and flavivirus. All priority RNA viruses encode a viral helicase domain in their genomes, and they share high similarity in structure and biochemical features. Viral RNA helicase is a critical component of the viral replicase complex and is essential for RNA virus replication. Further, it shows a high sequence homology within the virus family (e.g., 100% identity within SARS2). Consequently, viral RNA helicases can serve as a novel antiviral target for RNA viruses with a high barrier to drug resistance. During the past 10 years, the Chung lab has made significant contributions to the development of antivirals targeting the alphavirus helicase domain (nsP2) and validated viral helicase as druggable for developing potent antivirals. Based on this success, we hypothesize the viral helicase can serve as a valid target for safe and effective antivirals for SARS2 and other priority RNA viruses. Here, we propose a comprehensive antiviral discovery campaign targeting viral helicase with a multi-disciplinary approach combining ultra-high-throughput screening and DNA-Encoded Chemistry Technology followed by a robust hit validation scheme with antiviral testing, structural biology, and biochemical approaches (Aim 1). Further, we propose to advance promising viral helicase inhibitor hits through hit-to-lead development, giving validated leads as drug development candidates with medicinal chemistry paired with AI-based drug design, DMPK studies, and in vivo antiviral efficacy studies (Aim 2). Finally, we will deliver 1-2 orally bioavailable, patentable, druglike IND-enabled small molecules (a development candidate + backup) that are well-suited for translation by a pharma partner (Aim 3). Our proposal is supported by our discovery of a novel hit compound (UNC0379) with an anti-SARS2 activity from a pilot 100,000-compound library screen (Core B). The PI and established team (Chung, virology/PI; Bannister, Med. Chem/deputy; Spicer, uHTS; Luo, structural biology of viral replicase; Raney, helicase biochemistry) synergistically combine antiviral drug discovery (Head-Gordon, Compchem/AI) with excellent core support (Core B and Core C). Our effort will deliver new classes of direct helicase-targeting antiviral agents for SARS2 infection and other high priority viral pathogens.

项目 5 – 大流行病毒解旋酶抑制剂 抽象的 该项目的目标是开发针对病毒解旋酶的泛家族抗病毒候选药物 冠状病毒和黄病毒。所有优先RNA病毒在其基因组中编码病毒解旋酶结构域，并且它们 结构和生化特征高度相似。病毒RNA解旋酶是病毒的重要组成部分 复制酶复合体对于 RNA 病毒复制至关重要。此外，它显示出高度的序列同源性 病毒家族（例如 SARS2 内 100% 同一性）。因此，病毒RNA解旋酶可以作为一种新的解旋酶。 RNA病毒的抗病毒靶标，具有高度耐药性。在过去的 10 年里，Chung 实验室 为针对甲病毒解旋酶结构域的抗病毒药物的开发做出了重大贡献 (nsP2) 并验证病毒解旋酶可用于开发有效的抗病毒药物。基于这一成功，我们 假设病毒解旋酶可以作为针对 SARS2 和其他病毒的安全有效抗病毒药物的有效靶标 优先RNA病毒。 在这里，我们提出了一项针对病毒解旋酶的全面抗病毒发现活动，采用多学科的方法 结合超高通量筛选和 DNA 编码化学技术的方法，然后 具有抗病毒测试、结构生物学和生化方法的稳健命中验证方案（目标 1）。 此外，我们建议通过从命中到先导的开发来推进有希望的病毒解旋酶抑制剂命中，从而给予 通过药物化学与基于人工智能的药物设计相结合，将先导化合物验证为药物开发候选药物， DMPK 研究和体内抗病毒功效研究（目标 2）。最后，我们将提供 1-2 种口服生物可利用的药物， 可申请专利、类似药物 IND 启用的小分子（开发候选者 + 备用）非常适合 由制药合作伙伴翻译（目标 3）。我们的提议得到了我们发现的一种新型热门化合物的支持 (UNC0379)，具有来自试点 100,000 种化合物库筛选的抗 SARS2 活性（核心 B）。 PI 和 建立的团队（Chung，病毒学/PI；Bannister，医学化学/副；Spicer，uHTS；Luo，结构生物学 病毒复制酶； Raney，解旋酶生物化学）协同地结合抗病毒药物发现（Head-Gordon， Compchem/AI）具有出色的核心支持（Core B 和 Core C）。我们的努力将提供新的直接课程 针对 SARS2 感染和其他高优先级病毒病原体的解旋酶靶向抗病毒药物。