Structural basis of main proteases of MERS-CoV bound to antineoplastic drug carmofur.

Recurrent epidemics of coronaviruses have posed significant threats to human life and health. The mortality rate of patients infected with the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is 35 %. The main protease (M) plays a crucial role in the MERS-CoV life cycle, and M exhibited a high degree of conservation among different coronaviruses. Therefore inhibition of M has become an effective strategy for the development of broad-spectrum anti-coronaviral drugs. The inhibition of SARS-CoV-2 M by the anti-tumor drug carmofur has been revealed, but structural studies of carmofur in complex with M from other types of coronavirus have not been reported. Hence, we revealed the structure of the MERS-CoV M-carmofur complex, analysed the structural basis for the binding of carmofur to MERS-CoV M in detail, and compared the binding patterns of carmofur to Ms of two different coronaviruses, MERS-CoV and SARS-CoV-2. Considering the importance of Ms for coronavirus therapy, structural understanding of M inhibition by carmofur could contribute to the design and development of novel antiviral drugs with safe and broad-spectrum efficacy.