The coronavirus SARS-CoV-2 causes the current outbreak of the respiratory disease COVID-19. Antiviral medication to treat COVID-19 is urgently needed. A possible drug target in coronaviruses is the main protease (M^pro also called 3CL^pro), an enzyme that is essential for replication of the virus.

Rolf Hilgenfeld, University of Lübeck, Germany, and colleagues have recently designed and synthesized peptidomimetic α-ketoamides to be used as inhibitors of the main proteases of coronaviruses. To allow the design of improved α-ketoamide inhibitors, the researchers have determined the crystal structure of the M^pro of SARS-CoV-2 at a resolution of 1.75 Å using X-ray crystallography.

The structure is very similar to the M^pro of the related SARS virus. It is a dimer that features six-stranded antiparallel β-barrels, with the substrate-binding site between them, and a cluster of five helices involved in dimerization of the enzyme. The team used the crystal structure to investigate the interactions of M^pro with α-ketoamides and optimize the substituents of the drug candidates. They obtained a potent inhibitor of the SARS-CoV-2 M^pro. The optimized drug candidate showed promising properties in a mouse study: It remains in the lung tissue for some time and could potentially be administered directly by inhalation.

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• Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors,
  Linlin Zhang, Daizong Lin, Xinyuanyuan Sun, Ute Curth, Christian Drosten, Lucie Sauerhering, Stephan Becker, Katharina Rox, Rolf Hilgenfeld,
  Science 2020.
  https://doi.org/10.1126/science.abb3405

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