Inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 main protease by tafenoquine in vitro

Chen, Y.; Yang, W.-H.; Huang, L.-M.; Wang, Y.-C.; Yang, C.-S.; Liu, Y.-L.; Hou, M.-H.; Tsai, C.-L.; Chou, Y.-Z.; Huang, B.-Y.; Hung, C.-F.; Hung, Y.-L.; Chen, J.-S.; Chiang, Y.-P.; Cho, D.-Y.; Jeng, L.-B.; Tsai, C.-H.; Hung, M.-C.

doi:10.1101/2020.08.14.250258

bioRxiv · 10.1101/2020.08.14.250258

Inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 main protease by tafenoquine in vitro

Chen, Y.·Yang, W.-H.·Huang, L.-M.·Wang, Y.-C.·Yang, C.-S.·Liu, Y.-L.·Hou, M.-H.·Tsai, C.-L.·Chou, Y.-Z.·Huang, B.-Y.·Hung, C.-F.·Hung, Y.-L.·Chen, J.-S.·Chiang, Y.-P.·Cho, D.-Y.·Jeng, L.-B.·Tsai, C.-H.·Hung, M.-C.

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Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the current pandemic, coronavirus disease 2019 (COVID-19), has taken a huge toll on human lives and the global economy. Therefore, effective treatments against this disease are urgently needed. Here, we established a fluorescence resonance energy transfer (FRET)-based high-throughput screening platform to screen compound libraries to identify drugs targeting the SARS-CoV-2 main protease (Mpro), in particular those which are FDA-approved, to be used immediately to treat patients with COVID-19. Mpro has been shown to be one of the most important drug targets among SARS-related coronaviruses as impairment of Mpro blocks processing of viral polyproteins which halts viral replication in host cells. Our findings indicate that the anti-malarial drug tafenoquine (TFQ) induces significant conformational change in SARS-CoV-2 Mpro and diminishes its protease activity. Specifically, TFQ reduces the -helical content of Mpro, which converts it into an inactive form. Moreover, TFQ greatly inhibits SARS-CoV-2 infection in cell culture system. Hence, the current study provides a mechanistic insight into the mode of action of TFQ against SARS-CoV-2 Mpro. Moreover, the low clinical toxicity of TFQ and its strong antiviral activity against SARS-CoV-2 should warrant further testing in clinical trials.

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Chen, Y., Yang, W.-H., Huang, L.-M., Wang, Y.-C., Yang, C.-S., Liu, Y.-L., Hou, M.-H., Tsai, C.-L., Chou, Y.-Z., Huang, B.-Y., Hung, C.-F., Hung, Y.-L., Chen, J.-S., Chiang, Y.-P., Cho, D.-Y., Jeng, L.-B., Tsai, C.-H., Hung, M.-C.. 2020-08-15. Inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 main protease by tafenoquine in vitro. https://doi.org/10.1101/2020.08.14.250258

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