7DDC

Crystal structure of SARS-CoV-2 main protease in complex with Tafenoquine

Summary for 7DDC

• Entry DOI: 10.2210/pdb7ddc/pdb
• Descriptor: 3C-like proteinase, Tafenoquine (3 entities in total)
• Functional Keywords: main protease, 3c-like proteinase, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• Total number of polymer chains: 1
• Total formula weight: 34346.09

Authors

Chen, Y.,Wang, Y.C.,Yang, C.S.,Hung, M.C. (deposition date: 2020-10-28, release date: 2021-11-10, Last modification date: 2023-11-29)

Primary citation

Chen, Y.,Yang, W.H.,Chen, H.F.,Huang, L.M.,Gao, J.Y.,Lin, C.W.,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.,Wang, W.J.,Su, W.C.,Kumar, V.,Wu, Y.C.,Chao, S.W.,Chang, C.S.,Chen, J.S.,Chiang, Y.P.,Cho, D.Y.,Jeng, L.B.,Tsai, C.H.,Hung, M.C.
Tafenoquine and its derivatives as inhibitors for the severe acute respiratory syndrome coronavirus 2.
J.Biol.Chem., 298:101658-101658, 2022

PubMed Abstract: 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), 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 M protease activity. The crystal structure of SARS-CoV-2 M in complex with TFQ revealed that TFQ noncovalently bound to and reshaped the substrate-binding pocket of M 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 transmembrane protease serine 2 (TMPRSS2). Furthermore, one TFQ derivative, compound 7, showed a better therapeutic index 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.

PubMed: 35101449
DOI: 10.1016/j.jbc.2022.101658

Experimental method

X-RAY DIFFRACTION (2.175 Å)