The coronavirus disease 2019 (COVID-19) pandemic severely impacts health, economy, and society worldwide. Antiviral drugs against SARS-CoV-2 are urgently needed to cope with this global crisis. It has been found that the biogenesis and release mechanisms of viruses share a common pathway with extracellular vesicles (EVs). We hypothesized that small molecule inhibitors of EV biogenesis/release could exert an anti-SARS-CoV-2 effect. Here, we screened 17 existing EV inhibitors and found that calpeptin, a cysteine proteinase inhibitor, exhibited the most potent anti-SARS-CoV-2 activity with no apparent cytotoxicity. Calpeptin demonstrated the dose-dependent inhibition against SARS-CoV-2 viral nucleoprotein expression in the infected cells with a half-maximal inhibitory concentration (IC50) of 1.44 µM in Vero-E6 and 26.92 µM in Calu-3 cells, respectively. Moreover, calpeptin inhibited the production of infectious virions with the lower IC50 of 0.6 µM in Vero E6 cells and 10.12 µM in Calu-3 cells. Interestingly, a combination of calpeptin and remdesivir, the FDA-approved antiviral drug against SARS-CoV-2 viral replication, significantly enhanced the anti-SARS-CoV-2 effects compared to monotherapy. This study discovered calpeptin as a promising candidate for anti-SARS-CoV-2 drug development. Further preclinical and clinical studies are warranted to elucidate the therapeutic efficacy of calpeptin and remdesivir combination in COVID-19.
【저자키워드】 COVID-19, SARS-CoV-2, Antiviral, Remdesivir, Extracellular vesicles, inhibitors, Combination, calpeptin, 【초록키워드】 coronavirus disease, pandemic, cytotoxicity, drug, virus, anti-SARS-CoV-2, IC50, antiviral drug, Health, Impact, pathway, extracellular vesicle, Vero E6 cell, inhibitor, monotherapy, expression, clinical study, Anti-SARS-CoV-2 Activity, calu-3 cells, cysteine, half-maximal inhibitory concentration, therapeutic efficacy, virion, SARS-CoV-2 viral replication, proteinase, infected cell, biogenesis, dose-dependent inhibition, Effect, EVs, VERO-E6, SARS-CoV-2 viral, significantly, inhibited, screened, exhibited, demonstrated, release mechanism, small molecule inhibitor, 【제목키워드】 Screening, activity, validation,