From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design

By Rolf Hilgenfeld. The FEBS Journal, 2014

615 citations recorded by the source corpus.

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.

Subfields: Computational Theory and Mathematics, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/cbdb48cde9bb60e61f215e76e00f32f36562f46e

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In Computational Theory and Mathematics

In Infectious Diseases

Citations in the corpus

SARS and MERS: recent insights into emerging coronaviruses (2016, positive): “This inhibitor, named SG85, indeed inhibits MERS-CoV replication in vitro 112 .”
Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors (2020, background): “An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of its essential role in processing the polyproteins that are translated from the viral RNA.”
Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein (2017, background): “For example, this loop comprises 6 amino-acid residues (GNYQCG) in SARS-CoV PL2 pro but 7 (GIETAVG) in the enzyme of MERS-CoV, leading to the inability of SARS-CoV PL pro inhibitors to act on MERS-CoV PL pro (Báez-Santos et al., 2014; Hilgenfeld, 2014; Lee et al., 2015) .”
The Molecular Docking Study of Potential Drug Candidates Showing Anti-COVID-19 Activity by Exploring of Therapeutic Targets of SARS-CoV-2 (2020, background): “It can generate mature protein, which facilitates replication[27, 28] and also helps to release NSPs.”
Fast Identification of Possible Drug Treatment of Coronavirus Disease −19 (COVID-19) Through Computational Drug Repurposing Study (2020, methodology): “45 The structure of SARS-CoV-2 main protease is found to be most similar to those of SARS-CoV protease (PDB 3TNT 46 ) and less similar to MERS-CoV protease (PDB 5WKK 47 ) ( Figure 9A ).”