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

Chen, Yeh; Yang, Wen-Hao; Huang, Li-Min; Wang, Yu-Chuan; Yang, Chia-Shin; Liu, Yi-Liang; Hou, Mei-Hui; Tsai, Chia-Ling; Chou, Yi-Zhen; Huang, Bao-Yue; Hung, Chian-Fang; Hung, Yu-Lin; Chen, Jin-Shing; Chiang, Yu-Ping; Cho, Der-Yang; Jeng, Long-Bin; Tsai, Chang-Hai; Hung, Mien-Chie

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 α-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.