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 该项目的目的是开发针对病毒解旋酶的泛家庭抗病毒药候选者 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 在结构和生化特征上具有很高的相似性。病毒RNA解旋酶是病毒的关键成分 复制酶复合物，对于RNA病毒复制至关重要。此外，它显示了高序列的同源性 病毒家族（例如SARS2中的100％身份）。因此，病毒RNA解旋酶可以用作新颖 RNA病毒的抗病毒靶标具有耐药性较高的较高障碍。在过去的10年中，Chung Lab 已经为针对αThavirus旋转酶域的抗病毒药的发展做出了重大贡献 （NSP2）并验证了病毒解旋酶，作为用于开发潜在抗病毒药的药物。基于这一成功，我们 假设病毒解旋酶可以作为SARS2和其他其他的安全有效抗病毒药的有效目标 优先RNA病毒。 在这里，我们提出了一个全面的抗病毒发现运动，以多学科的方式针对病毒解旋酶 结合超高通量筛选和DNA编码化学技术的方法 抗病毒测试，结构生物学和生化方法的强大命中验证方案（AIM 1）。 此外，我们建议通过命中率开发来推动有希望的病毒解旋酶抑制剂击中，从而使 经过验证的潜在客户作为药物开发候选者，具有医学化学的候选者，与基于AI的药物设计配对， DMPK研究和体内抗病毒效率研究（AIM 2）。最后，我们将提供1-2个口头的生物利用度， 非常适合适合的专利的，具有毒品的毒品状成型小分子（开发候选 +备份） 制药合作伙伴的翻译（AIM 3）。我们发现了一个新颖的热门化合物，我们的建议得到了支持 （UNC0379）具有100,000个混合图书馆屏幕（Core B）的抗SARS2活性。 pi和 成立团队（Chung，病毒学/PI； Bannister，Med。Chem/Chem副手； Spicer，UHTS; Luo，Luo，结构生物学 病毒复制酶； Raney，解旋酶生物化学）协同合并抗病毒药物发现（头盖顿， 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类 用于SARS2感染和其他高优先病毒病原体的解旋酶靶向抗病毒剂。