Project 5: Pandemic Virus Helicase Inhibitors

项目5：大流行病毒解旋酶抑制剂

基本信息

批准号：
10674237
负责人：
Donghoon Chung
金额：
$ 45.68万
依托单位：
UNIVERSITY OF MINNESOTA
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/10674237
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

项目摘要

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。病毒RNA解旋酶在结构和生化特征上具有高度相似性，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，经过测试，病毒 RNA 解旋酶与 SARS2 具有 100% 的同一性）。在过去的10年里，Chung实验室研究了具有高耐药性的RNA病毒的抗病毒靶标。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) 并验证了病毒解旋酶可用于开发有效的抗病毒药物。维持病毒解旋酶可以作为安全有效的抗 SARS2 和其他病毒药物的有效靶点优先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，最后，我们将提供 1-2 种口服生物可利用的、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）。我们发现了一种新型热门化合物，这支持了我们的建议。 (UNC0379) 具有来自试点 100,000 种化合物库筛选的抗 SARS2 活性（核心 B）。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）协同结合抗病毒药物发现（Head-Gordon， Compchem/AI）具有出色的核心支持（核心 B 和核心 C），我们的努力将提供新的直接类别。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。