A Structural View of the Inactivation of the SARS Coronavirus Main Proteinase by Benzotriazole Esters

Koen H G Verschueren; Ksenia Pumpor; Stefan Anemüller; Shuai Chen; Jeroen R. Mesters; Rolf Hilgenfeld

doi:10.1016/j.chembiol.2008.04.011

A Structural View of the Inactivation of the SARS Coronavirus Main Proteinase by Benzotriazole Esters

Koen H G Verschueren, Ksenia Pumpor, Stefan Anemüller, Shuai Chen, Jeroen R. Mesters, Rolf Hilgenfeld^*

^*Corresponding author for this work

Institute of Biochemistry

35 Citations (Scopus)

Abstract

The main proteinase (M ^pro) of the severe acute respiratory syndrome (SARS) coronavirus is a principal target for the design of anticoronaviral compounds. Benzotriazole esters have been reported as potent nonpeptidic inhibitors of the enzyme, but their exact mechanism of action remains unclear. Here we present crystal structures of SARS-CoV M ^pro, the active-site cysteine of which has been acylated by benzotriazole esters that act as suicide inhibitors. In one of the structures, the thioester product has been hydrolyzed and benzoic acid is observed to bind to the hydrophobic S2 pocket. This structure also features the enzyme with a shortened N-terminal segment ("amputated N finger"). The results further the understanding of the important role of the N finger for catalysis as well as the design of benzotriazole inhibitors with improved specificity.

Original language	English
Journal	Chemistry and Biology
Volume	15
Issue number	6
Pages (from-to)	597-606
Number of pages	10
ISSN	1074-5521
DOIs	https://doi.org/10.1016/j.chembiol.2008.04.011
Publication status	Published - 23.06.2008

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Academic Focus: Center for Infection and Inflammation Research (ZIEL)

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chembiol.2008.04.011

Cite this

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abstract = "The main proteinase (M pro) of the severe acute respiratory syndrome (SARS) coronavirus is a principal target for the design of anticoronaviral compounds. Benzotriazole esters have been reported as potent nonpeptidic inhibitors of the enzyme, but their exact mechanism of action remains unclear. Here we present crystal structures of SARS-CoV M pro, the active-site cysteine of which has been acylated by benzotriazole esters that act as suicide inhibitors. In one of the structures, the thioester product has been hydrolyzed and benzoic acid is observed to bind to the hydrophobic S2 pocket. This structure also features the enzyme with a shortened N-terminal segment ({"}amputated N finger{"}). The results further the understanding of the important role of the N finger for catalysis as well as the design of benzotriazole inhibitors with improved specificity.",

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AU - Verschueren, Koen H G

AU - Pumpor, Ksenia

AU - Anemüller, Stefan

AU - Chen, Shuai

AU - Mesters, Jeroen R.

AU - Hilgenfeld, Rolf

PY - 2008/6/23

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AB - The main proteinase (M pro) of the severe acute respiratory syndrome (SARS) coronavirus is a principal target for the design of anticoronaviral compounds. Benzotriazole esters have been reported as potent nonpeptidic inhibitors of the enzyme, but their exact mechanism of action remains unclear. Here we present crystal structures of SARS-CoV M pro, the active-site cysteine of which has been acylated by benzotriazole esters that act as suicide inhibitors. In one of the structures, the thioester product has been hydrolyzed and benzoic acid is observed to bind to the hydrophobic S2 pocket. This structure also features the enzyme with a shortened N-terminal segment ("amputated N finger"). The results further the understanding of the important role of the N finger for catalysis as well as the design of benzotriazole inhibitors with improved specificity.

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A Structural View of the Inactivation of the SARS Coronavirus Main Proteinase by Benzotriazole Esters

Abstract

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