Midwest AViDD Center

中西部 AViDD 中心

• 批准号: 10631659
• 负责人: Reuben S Harris
• 金额: $ 45.68万
• 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/10631659
• 关键词: 2019-nCoV; Alphavirus; Animal Model; Animals; Anti-Inflammatory Agents; Antibodies; Antiviral Agents; Autopsy; Biochemical; Biochemistry; Blood Circulation; COVID-19 therapeutics; COVID-19 treatment; Cells; Chemistry; Clinical; Complex; Containment; Coronavirus; DNA; Data; Detection; Development; Disease Progression; Disease model; Dose; Drug Design; Drug resistance; Evaluation; Family; Flavivirus; Future; Genome; Goals; Grant; Head; Histocytochemistry; ITGAM gene; Imaging Device; Imaging technology; Immune; ImmunoPET; Immunology; Immunology procedure; Infectious Agent; Inflammation; Inflammatory; K-18 conjugate; Kinetics; Lead; Libraries; Life; Lung; Metabolic; Midwestern United States; Mission; Modeling; Molecular; Monitor; Monoclonal Antibodies; Mus; Neutrophilic Infiltrate; Oral; Outcome; PET/CT scan; Pathogenesis; Peptide Hydrolases; Pharmaceutical Chemistry; Polymerase; Population; Positron; Positron-Emission Tomography; Pulmonary Inflammation; RNA Helicase; RNA Viruses; Radiochemistry; Radioisotopes; Research; SARS-CoV-2 antiviral; SARS-CoV-2 infection; Scheme; Sequence Homology; Specificity; Spices; Structure; Techniques; Technology; Testing; Therapeutic; Translations; Tumor-infiltrating immune cells; Universities; Validation; Viral; Virus; Virus Diseases; Virus Replication; X-Ray Computed Tomography; Zika Virus; anti-viral efficacy; antiviral drug development; base; clinical translation; drug candidate; drug development; drug discovery; efficacy study; fluorodeoxyglucose; helicase; high throughput screening; imaging modality; imaging probe; in vivo; in vivo imaging; inhibitor; interdisciplinary approach; longitudinal analysis; macrophage; molecular imaging; monocyte; mouse model; neutrophil; non-invasive imaging; novel; pandemic disease; pathogenic virus; remdesivir; replicase; severe COVID-19; single photon emission computed tomography; small molecule; specific biomarkers; structural biology; success; translational study; viral RNA; virology; whole body imaging

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 摘要 该项目的目标是开发针对病毒解旋酶的泛家族抗病毒药物候选药物。 冠状病毒和黄病毒。所有优先的RNA病毒都在它们的基因组中编码一个病毒解旋酶结构域，它们 在结构和生化特征上具有很高的相似性。病毒RNA解旋酶是病毒的重要组成部分 复制酶复合体，是RNA病毒复制所必需的。此外，它还显示了内部的高度序列同源性 病毒家族(例如，SARS2中的100%身份)。因此，病毒RNA解旋酶可以作为一种新的 针对具有高耐药性屏障的RNA病毒的抗病毒靶标。在过去的10年里，Chung实验室 在针对甲型病毒解旋酶结构域的抗病毒药物的开发方面做出了重大贡献 (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安全有效的SARS2和其他抗病毒药物的有效靶点 优先RNA病毒。 在这里，我们提出了一个多学科的针对病毒解旋酶的全面的抗病毒发现活动 超高通量筛选和DNA编码化学技术相结合的方法 稳健的HIT验证方案，包括抗病毒测试、结构生物学和生化方法(目标1)。 此外，我们建议通过Hit-to-Lead开发来推进有前景的病毒解旋酶抑制剂HITS，给出 药物化学与基于人工智能的药物设计相结合的药物开发候选验证线索， DMPK研究和体内抗病毒疗效研究(目标2)。最后，我们将提供1-2个口服生物利用度， 可申请专利的、类似药物的、支持IND的小分子(候选开发+备份)，非常适合 由制药合作伙伴进行翻译(目标3)。我们发现了一种新的热门化合物，这支持了我们的建议 (Unc0379)具有来自试点100,000化合物库屏幕(核心B)的抗SARS2活性。圆周率和 已建立的团队(钟，病毒学/PI；班尼斯特，医学首页--期刊主要分类--期刊细介绍--期刊题录与文摘内容 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 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。

项目成果

Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors.

• DOI: 10.1126/sciadv.ade8778
• 发表时间: 2023-03-29
• 期刊: LANCET INFECTIOUS DISEASES
• 影响因子: 56.3
• 作者: Devi, Sharmila

Rapid resistance profiling of SARS-CoV-2 protease inhibitors.

SARS-CoV-2 蛋白酶抑制剂的快速耐药性分析。

• DOI: 10.21203/rs.3.rs-2627723/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Moghadasi,SeyedArad;Biswas,RayhanG;Harki,DanielA;Harris,ReubenS
• 通讯作者: Harris,ReubenS

Flavivirus nonstructural proteins and replication complexes as antiviral drug targets.

• DOI: 10.1016/j.coviro.2023.101305
• 发表时间: 2023-03
• 期刊: Current opinion in virology
• 影响因子: 5.9
• 作者: Kaïn van den Elsen;Bing Liang Alvin Chew;J. Ho;D. Luo