Evaluation of Artemisia as an Effective Combination Therapy Against SARS-CoV-2 Infection

摘要 病毒非常危险；它们从一个物种跳到另一个物种，变异以躲避疫苗和单一的抗病毒药物。 毒品，并导致许多人类疾病和死亡。目前一个臭名昭著的例子是严重急性呼吸系统 冠状病毒2型综合征(SARS-CoV-2)。正如我们每天看到的那样，冠状病毒大流行暴露出巨大的漏洞 在美国的医疗体系中，以及我们对广泛传播的病毒爆发的准备是多么悲哀。两年 在这次大流行中，我们有三种抗病毒药物(瑞希韦、莫努比拉韦和巴昔洛韦)和一种抗炎药物(地塞米松)。因此，对抗病毒和感染的炎症性后遗症的药物需求仍然没有得到满足。最近可获得的疫苗有助于阻止这一大流行，但推广、分发、疫苗的迟疑以及持续出现的关注变种阻碍了实现这一目标的进展。由于这些不确定性，许多人转向了具有 希望这些未经测试的补充剂能让他们保持安全和健康。事实上，近20%的美国人口使用天然产品(包括植物性或植物性制剂)来治疗或预防疾病。植物性药物的使用在资源有限的国家更为普遍，对许多人来说，这些药物构成了一种初级保健方式。这一R21建议源于我们团队最近的一项发现，即从植物黄花蒿(Asteraceae)(又名青蒿，青蒿素，苦艾， 一年生艾草，甜蜜安妮)，在体外有效地抑制野生型SARS-CoV-2和VOC的感染。根据我们最近发表的初步数据，我们假设黄花菇含有在体内协同抑制SARS-CoV-2和病毒诱导的炎症的化合物的混合物。为了解决这一假设，Weather、Polyak、Fuller和Kellogg实验室将合并他们在植物民族药理学(历史上使用的药用植物的药理学)、体外和体内病毒学以及天然产品方面的互补专业知识。 在SARS-CoV-2感染和疾病的人ACE-2转基因小鼠模型(AIM 1)中，进行两个特定的目的来证明黄花丹提取物的体内抗病毒活性。我们还将a)定义具有抗病毒活性的天然产物(S)，b)是否通过青蒿中化合物的协同组合产生病毒抑制，以及c)开始破译抗病毒作用的机制(AIM 2)。因此，该项目有望为抗击新冠肺炎的战斗提供新的工具，并可能加强全球对下一次病毒爆发的准备，历史告诉我们，下一次病毒爆发是肯定会发生的。

ABSTRACT 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 current example is Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). As we witness daily, the coronavirus pandemic reveals gaping holes in the US healthcare system and how woefully unprepared we are for wide-spread viral outbreaks. Two years into the pandemic we have three antiviral drugs (remdesivir, molnupiravir, and paxlovid and a single anti-inflammatory (dexamethasone). Thus, there remains an unmet need for drugs to fight the virus and the inflammatory sequelae of infection. Recently available vaccines comprise a boon to stopping this pandemic, but rollout, distribution, vaccine hesitancy, and the continuing emergence of variants of concern (VOC) hinder progress towards this goal. Because of these uncertainties, 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 (including plant-based or botanical preparations) for treatment or prevention of disease. The use of plant-based medicines is even more prevalent in resource-limited countries, where for many people they constitute a primary health care modality. This R21 proposal stems from the recent finding by our team that extracts from the plant Artemisia annua L. (Asteraceae) (aka A. annua, qinghao, sweet wormwood, annual wormwood, sweet annie), potently inhibits wild type SARS-CoV-2 and VOC infection in vitro. Based on our recently published and preliminary data, we hypothesize that A. annua contains mixtures of compounds that synergistically inhibit SARS-CoV-2 and virus-induced inflammation in vivo. To address the hypothesis, the Weathers, Polyak, Fuller, and Kellogg labs will merge their complementary expertise in plant ethnopharmacology the pharmacology of historically used medicinal plants), in vitro and in vivo virology, and natural product chemistry, and to conduct two Specific Aims that will demonstrate the in vivo antiviral activity of A. annua extracts in the human ACE-2 transgenic mouse model of SARS-CoV-2 infection and disease (AIM 1). We will also a) define the natural product(s) that confer antiviral activity, b) whether virus suppression arises through synergistic combinations of compounds in A. annua, and c) begin to decipher mechanisms of antiviral action (AIM 2). As such, this project is expected to provide new tools for the battle against COVID-19 and potentially enhance global preparedness for the next virus outbreak, which history has taught us will most certainly occur.