Tafenoquine and its derivatives as inhibitors for the severe acute respiratory syndrome coronavirus 2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has severely affected human lives around the world as well as the global economy. Therefore, effective treatments against COVID-19 are urgently needed. Here, we screened a library containing Food and Drug Administration (FDA)-approved compounds to identify drugs that could target the SARS-CoV-2 main protease (M-pro), which is indispensable for viral protein maturation and regard as an important therapeutic target. We identified antimalarial drug tafenoquine (TFQ), which is approved for radical cure of Plasmodium vivax and malaria prophylaxis, as a top candidate to inhibit Mpro protease activity. The crystal structure of SARS-CoV-2 M-pro in complex with TFQ revealed that TFQ non-covalently bound to and reshaped the substrate-binding pocket of Mpro by altering the loop region (residues 139-144) near the catalytic Cys145, which could block the catalysis of its peptide substrates. We also found that TFQ inhibited human trans-membrane protease serine 2 (TMPRSS2). Furthermore, one TFQ derivative, compound 7, showed a better therapeutic in-dex than TFQ on TMPRSS2 and may therefore inhibit the infectibility of SARS-CoV-2, including that of several mutant variants. These results suggest new potential strategies to block infection of SARS-CoV-2 and rising variants.

Automated summary

This study screened a library of FDA-approved compounds and identified the antimalarial drug tafenoquine (TFQ) as a potential inhibitor of the SARS-CoV-2 main protease (M-pro). The crystal structure of the M-pro-TFQ complex revealed the binding and reshaping of the substrate-binding pocket, blocking the catalytic activity. TFQ was also found to inhibit a human trans-membrane protease. A derivative of TFQ, compound 7, showed improved efficacy in inhibiting protease activity and may therefore be effective against SARS-CoV-2 and its variants.