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

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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.