Structure of SARS-CoV-2 Main Protease as a Basis for Drug Design

Structure of SARS-CoV-2 Main Protease as a Basis for Drug Design


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 (Mpro also called 3CLpro), 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 Mpro of SARS-CoV-2 at a resolution of 1.75 Å using X-ray crystallography.

The structure is very similar to the Mpro 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 Mpro with α-ketoamides and optimize the substituents of the drug candidates. They obtained a potent inhibitor of the SARS-CoV-2 Mpro. 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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