Structural basis for the inhibition of COVID-19 virus main protease by carmofur, an antineoplastic drug

Jin, Z.; Zhao, Y.; Sun, Y.; Zhang, B.; Wang, H.; Wu, Y.; Zhu, Y.; Zhu, C.; Hu, T.; Du, X.; Duan, Y.; Yu, J.; Yang, X.; Liu, X.; Guddat, L. W.; Xiao, G.; Zhang, L.; Yang, H.; Rao, Z.

doi:10.1101/2020.04.09.033233

bioRxiv · 10.1101/2020.04.09.033233

Structural basis for the inhibition of COVID-19 virus main protease by carmofur, an antineoplastic drug

Jin, Z.·Zhao, Y.·Sun, Y.·Zhang, B.·Wang, H.·Wu, Y.·Zhu, Y.·Zhu, C.·Hu, T.·Du, X.·Duan, Y.·Yu, J.·Yang, X.·Liu, X.·Guddat, L. W.·Xiao, G.·Zhang, L.·Yang, H.·Rao, Z.

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Abstract

The antineoplastic drug Carmofur was shown to inhibit SARS-CoV-2 main protease (Mpro). Here the X-ray crystal structure of Mpro in complex with Carmofur reveals that the carbonyl reactive group of Carmofur is covalently bound to catalytic Cys145, whereas its fatty acid tail occupies the hydrophobic S2 subsite. Carmofur inhibits viral replication in cells (EC50 = 24.30 M) and it is a promising lead compound to develop new antiviral treatment for COVID-19.

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Jin, Z., Zhao, Y., Sun, Y., Zhang, B., Wang, H., Wu, Y., Zhu, Y., Zhu, C., Hu, T., Du, X., Duan, Y., Yu, J., Yang, X., Liu, X., Guddat, L. W., Xiao, G., Zhang, L., Yang, H., Rao, Z.. 2020-04-09. Structural basis for the inhibition of COVID-19 virus main protease by carmofur, an antineoplastic drug. https://doi.org/10.1101/2020.04.09.033233

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