Abstract
ABSTRACTCoronavirus disease 2019 (COVID-19) has caused huge deaths and economic losses worldwide in the current pandemic. The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is thought to be an ideal drug target for treating COVID-19. Leupeptin, a broad-spectrum covalent inhibitor of serine, cysteine, and threonine proteases, showed inhibitory activity against Mpro, with a 50% inhibitory concentration (IC50) value of 127.2 μM in vitro in our study here. In addition, leupeptin can also inhibit SARS-CoV-2 in Vero cells, with 50% effective concentration (EC50) values of 42.34 μM. More importantly, various strains of streptomyces that have a broad symbiotic relationship with medicinal plants can produce leupeptin and leupeptin analogs to regulate autogenous proteases. Fingerprinting and structure elucidation using high-performance liquid chromatography (HPLC) and high-resolution mass spectrometry (HRMS), respectively, further proved that the Qing-Fei-Pai-Du (QFPD) decoction, a traditional Chinese medicine (TCM) formula for the effective treatment of COVID-19 during the period of the Wuhan outbreak, contains leupeptin. All these results indicate that leupeptin at least contributes to the antiviral activity of the QFPD decoction against SARS-CoV-2. This also reminds us to pay attention to the microbiomes in TCM herbs as streptomyces in the soil might produce leupeptin that will later infiltrate the medicinal plant. We propose that plants, microbiome, and microbial metabolites form an ecosystem for the effective components of TCM herbs.
Highlights
Coronavirus disease 2019 (COVID-19) has caused huge deaths and economic losses worldwide in the current pandemic
We identified leupeptin, a metabolite produced by plant-symbiotic actinomyces (PSA), which showed antiviral activity in both cell culture and enzyme assays
High-performance liquid chromatography (HPLC) fingerprinting and high-resolution mass spectrometry (HRMS) showed that the Qing-Fei-Pai-Du (QFPD) decoction, a traditional Chinese medicine (TCM) formula, contains leupeptin. These results reveal that leupeptin may contribute to the QFPD decoction in the treatment of COVID-19, which had been popularly used in Wuhan in the first wave of the outbreak
Summary
Coronavirus disease 2019 (COVID-19) has caused huge deaths and economic losses worldwide in the current pandemic. We identified leupeptin, a metabolite produced by plant-symbiotic actinomyces (PSA), which showed antiviral activity in both cell culture and enzyme assays. Leupeptin found in the QFPD decoction was confirmed by both HPLC fingerprinting and HRMS. KEYWORDS SARS-CoV-2, main protease, leupeptin, TCM modernization research, plants, microbiome, and microbial metabolites ecosystem
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