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

项目总结 病毒是非常危险的；它们从一个物种跳到另一个物种，变异以躲避疫苗，并且单一 抗病毒药物，并导致许多人类疾病和死亡。一个臭名昭著的现在的例子是严重的 急性呼吸综合征冠状病毒-2(SARS-CoV-2；以下简称SARS-2)，我们所在的 在一场全球大流行中。正如我们每天目睹的那样，这场大流行揭示了美国经济的巨大漏洞 医疗体系，以及我们对病毒爆发的准备是多么可悲。虽然数十项临床试验正在进行 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 对抗病毒和感染的炎症性后遗症的药物。因此，许多人转向了 天然产品，希望这些未经测试的补充剂将使他们安全和健康。事实上，几乎 20%的美国人口使用天然产品来治疗或预防疾病。使用植物- 以药物为基础的药物在发展中国家更加普遍，对许多人来说，这些药物构成了 初级卫生保健模式。本次新冠肺炎竞争修订资金申请旨在 U41 AT008718-06，天然产物高通量功能注释中心(PI 将解决压倒一切的假设，即天然产品含有化合物的混合物 它主要通过靶向细胞来有效地抑制SARS-2和病毒引起的炎症。要解决这个问题 假设，切赫、麦克米兰和波利亚克实验室将把他们互补的专业知识整合到自然 产品生物化学计量学、基因图谱和病毒学，以进行两个特定的目标，将测试选定 使用生物安全水平(BSL)2兼容报告抑制病毒感染的天然产品提取物 使用SARS-2刺突蛋白进入细胞的伪病毒(目标1)。这一目标还将确定两个-和 由天然产物和FDA批准的药物的混合物组成的三种化合物增效剂 显示出抗SARS-2和广谱抗病毒活性。在目标2中，最有效的提取物和 在BSL3控制下，这些组合将针对完全传染性的SARS-2进行验证。自然的 在U41中分析的产品将优先进行分析。用这种方法，很有希望 抗病毒天然产品或提取物将具有互补的融合和细胞学特征，以便 我们将立即深入了解细胞参与和行动的机制。因为天然产品 众所周知，它们利用人类细胞提供细胞保护，而且由于许多病毒利用类似的 进入和离开细胞的途径，我们的创新方法和结果也可能对其他新兴的 以及再次出现的感染。因此，我们的务实做法将有助于对抗新冠肺炎，提升全球竞争力 为下一次病毒爆发做好准备。

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.