Urgent Covid-19 Revision to the Center for High-Throughput Functional Annotation of Natural Products

Covid-19 天然产物高通量功能注释中心紧急修订

• 批准号: 10212767
• 负责人: JOHN B MACMILLAN
• 金额: $ 24.19万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10212767
• 关键词: 2019-nCoV; Address; Amodiaquine; Anthelmintics; Anti-Inflammatory Agents; Antidepressive Agents; Antiinflammatory Effect; Antimalarials; Antiviral Agents; Arenavirus; Award; COVID-19; CXCL10 gene; Cells; Cessation of life; Chemicals; Chloroquine; Clinical; Clinical Research; Clinical Trials; Communities; Containment; Coronavirus; Cytology; Cytoprotection; Dangerousness; Data; Developing Countries; Disease; Disease Outbreaks; Doctor of Philosophy; Drug Combinations; Ebola; Ebola virus; Emergency Situation; Endosomes; FDA approved; Filovirus; Funding; Funding Agency; Goldenseal; Green tea; Healthcare Systems; Hepatitis C virus; Human; Hydroxychloroquine; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Light; Link; Mediating; Medicine; Meta-Analysis; Modality; Mutate; Natural Product Drug; Natural Products; Natural Products Chemistry; Pathway interactions; Patients; Pharmaceutical Preparations; Plague; Plants; Population; Preparation; Primary Health Care; Proteins; Publishing; Readiness; Reporter; Sertraline; Severe Acute Respiratory Syndrome; TNF gene; Testing; Toremifene; Vaccines; Vinorelbine; Viral; Viral Hemagglutinins; Virus; Virus Diseases; Work; Zika Virus; anti-cancer; anti-influenza; base; cytokine release syndrome; cytotoxic; disorder prevention; experience; fighting; genetic profiling; human disease; indexing; influenzavirus; innovation; insight; novel; pandemic disease; response; success; synergism; virology

PROJECT SUMMARY Viruses are cleverly dangerous; they jump from species to species, mutate to evade vaccines and single antiviral drugs, and cause many human diseases and deaths. A notorious and current example is Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2; hereafter abbreviated SARS-2), of which we are in the midst of a global pandemic. As we are witnessing daily, the pandemic reveals the gaping holes in the US’s healthcare system and how woefully unprepared we are for viral outbreaks. While dozens of clinical trials are ongoing, we still do not yet have effective and widely available vaccines and antiviral or anti-inflammatory drugs to fight the virus and the inflammatory sequelae of infection. As such, many people have turned to natural products with the hope that these untested supplements will keep them safe and healthy. In fact, nearly 20% of the US population uses natural products for treatment or prevention of disease. The use of plant- based medicines is even more prevalent in developing countries, where for many people they constitute the primary health care modality. This COVID-19 Emergency Competitive Revision funding request to U41 AT008718-06, The Center for High-Throughput Functional Annotation of Natural Products (PI MacMillan), will address the over-riding hypothesis that natural products contain mixtures of compounds that potently inhibit SARS-2 and virus-induced inflammation primarily by targeting the cell. To address the hypothesis, the Cech, MacMillan, and Polyak labs will merge their complementary expertise in natural product biochemometrics, genetic profiling, and virology to conduct two Specific Aims that will test selected natural product extracts for suppression of virus infection using Biosafety Level (BSL) 2-compatible reporter pseudoviruses that enter cells using the SARS-2 Spike protein (Aim 1). This aim will also identify two- and three-compound synergists consisting of mixtures of natural products and FDA approved drugs with demonstrated anti-SARS-2 and broad-spectrum antiviral activity. In Aim 2 the most potent extracts and combinations will be validated against fully infectious SARS-2 under BSL3 containment. The natural products being profiled in the U41 will be prioritized for analysis. With this approach, promising antiviral natural products or extracts will have complementary FUSION and cytological profiles such that we will gain immediate insight into mechanisms of cell engagement and action. Since natural products are well known to engage human cells to provide cytoprotection, and since many viruses engage similar pathways into and out of cells, our innovative approach and results may also work against other emerging and re-emerging infections. Thus, our practical approach will help battle COVID-19 and enhance global preparedness for the next virus outbreak.

项目摘要 病毒是聪明的危险;它们从一个物种跳到另一个物种，变异以逃避疫苗， 抗病毒药物，并导致许多人类疾病和死亡。一个臭名昭著的例子是严重的 急性呼吸道综合征冠状病毒-2（SARS-CoV-2;以下简称SARS-2），我们正处于其中 在一场全球流行病中。正如我们每天所目睹的那样，这场大流行揭示了美国在 医疗保健系统以及我们对病毒爆发的准备是多么的不足。尽管数十项临床试验 目前，我们仍然没有有效和广泛可用的疫苗和抗病毒或抗炎药物， 对抗病毒和感染后炎症的药物。因此，许多人转向 天然产品，希望这些未经测试的补充剂将保持他们的安全和健康。事实上， 20%的美国人使用天然产品来治疗或预防疾病。使用植物- 在发展中国家，基础药物更为普遍，对许多人来说， 初级卫生保健模式。本次COVID-19紧急竞争修订资金申请， U41 AT 008718 -06，天然产物高通量功能注释中心（PI MacMillan），将解决压倒一切的假设，即天然产品含有化合物的混合物 主要通过靶向细胞有效抑制SARS-2和病毒诱导的炎症。解决 假设，切赫，麦克米伦和波利亚克实验室将合并他们在自然科学领域的互补专业知识， 产品生物化学计量学，遗传分析和病毒学，以进行两个特定的目的，将测试选定的 使用生物安全水平（BSL）2相容的报告物抑制病毒感染的天然产物提取物 使用SARS-2刺突蛋白进入细胞的假病毒（Aim 1）。这一目标还将确定两个- 由天然产物和FDA批准的药物的混合物组成的三化合物增效剂， 具有抗SARS-2和广谱抗病毒活性。在目标2中，最有效的提取物和 将验证组合在BSL 3遏制下对抗完全传染性SARS-2。自然 在U41中被描述的产品将被优先分析。通过这种方法，有希望的 抗病毒天然产物或提取物将具有互补的融合和细胞学特征， 我们将立即深入了解细胞参与和行动的机制。由于天然产物 众所周知，与人类细胞结合以提供细胞保护，并且由于许多病毒与类似的 我们的创新方法和结果可能也会对其他新兴的细胞通路起作用。 和再次出现的感染因此，我们的务实方法将有助于抗击COVID-19，并提高全球 为下一次病毒爆发做好准备