Induced-Fit Binding of the Macrocyclic Noncovalent Inhibitor TMC435 to its HCV NS3/NS4A Protease Target

If the shoe fits: TMC435, a noncovalent small‐molecule inhibitor of the hepatitis C virus (HCV) NS3/NS4A protease, is currently undergoing clinical evaluation as an HCV therapeutic. In the crystal structure of the noncovalent NS3/NS4A protease–TMC435 complex the bound inhibitor exploits induced‐fit...

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Veröffentlicht in:	Angewandte Chemie (International ed.) 2010-02, Vol.49 (9), p.1652-1655
Hauptverfasser:	Cummings, Maxwell D, Lindberg, Jimmy, Lin, Tse -I, de Kock, Herman, Lenz, Oliver, Lilja, Elisabet, Felländer, Sara, Baraznenok, Vera, Nyström, Susanne, Nilsson, Magnus, Vrang, Lotta, Edlund, Michael, Rosenquist, Åsa, Samuelsson, Bertil, Raboisson, Pierre, Simmen, Kenneth
Format:	Artikel
Sprache:	eng
Schlagworte:	Binding Binding Sites Carrier Proteins - antagonists & inhibitors Carrier Proteins - metabolism Crystal structure Crystallography, X-Ray Drug Design hepatitis C Hepatitis C virus Heterocyclic Compounds, 3-Ring - chemistry Heterocyclic Compounds, 3-Ring - pharmacology Humans Inhibitors Macrocyclic compounds Macrocyclic Compounds - chemistry Protease Protease inhibitors Protease Inhibitors - chemistry Protease Inhibitors - pharmacology Protein Binding protein structures Simeprevir Sulfonamides - chemistry Sulfonamides - pharmacology Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - metabolism Viral Proteins - antagonists & inhibitors Viral Proteins - metabolism
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Zusammenfassung:	If the shoe fits: TMC435, a noncovalent small‐molecule inhibitor of the hepatitis C virus (HCV) NS3/NS4A protease, is currently undergoing clinical evaluation as an HCV therapeutic. In the crystal structure of the noncovalent NS3/NS4A protease–TMC435 complex the bound inhibitor exploits induced‐fit binding. The new structure is consistent with the emerging view of viral resistance to NS3/NS4A protease inhibitors.
ISSN:	1433-7851 1521-3773
DOI:	10.1002/anie.200906696