|| Checking for direct PDF access through Ovid
This review focuses on the important contributions that macromolecular crystallography has made over the past 12 years to elucidating structures and mechanisms of the essential proteases of coronaviruses, the main protease (Mpro) and the papain-like protease (PLpro). The role of X-ray crystallography in structure-assisted drug discovery against these targets is discussed. Aspects dealt with in this review include the emergence of the SARS coronavirus in 2002–2003 and of the MERS coronavirus 10 years later and the origins of these viruses. The crystal structure of the free SARS coronavirus Mpro and its dependence on pH is discussed, as are efforts to design inhibitors on the basis of these structures. The mechanism of maturation of the enzyme from the viral polyprotein is still a matter of debate. The crystal structure of the SARS coronavirus PLpro and its complex with ubiquitin is also discussed, as is its orthologue from MERS coronavirus. Efforts at predictive structure-based inhibitor development for bat coronavirus Mpros to increase the preparedness against zoonotic transmission to man are described as well. The paper closes with a brief discussion of structure-based discovery of antivirals in an academic setting.The coronavirus genome encodes two types of proteases, one chymotrypsin-like main protease and one or two papain-like protease(s), both of which are important targets for antiviral drug discovery. From just before the outbreak of the SARS coronavirus in 2002/2003 to the ongoing outbreak of MERS coronavirus, many crystal structures have been determined of these enzymes and their complexes with inhibitors, laying the basis for structure-based lead optimization.