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.