Mapping the Pro-Peptide of the Schistosoma mansoni Cathepsin B1 Drug Target: Modulation of Inhibition by Heparin and Design of Mimetic Inhibitors

0360455 - ÚOCHB 2012 RIV US eng J - Článek v odborném periodiku
Horn, Martin - Jílková, Adéla - Vondrášek, Jiří - Marešová, Lucie - Caffrey, C. R. - Mareš, Michael
Mapping the Pro-Peptide of the Schistosoma mansoni Cathepsin B1 Drug Target: Modulation of Inhibition by Heparin and Design of Mimetic Inhibitors.
ACS Chemical Biology. Roč. 6, č. 6 (2011), s. 609-617. ISSN 1554-8929. E-ISSN 1554-8937
Grant CEP: GA ČR GA203/09/1585; GA AV ČR KJB400550516; GA AV ČR IAA400550705
Grant ostatní: NATO(XE) NATO LST/CLG 980187
Výzkumný záměr: CEZ:AV0Z40550506
Klíčová slova: Schistosoma mansoni * cathepsin B * propeptide
Kód oboru RIV: CE - Biochemie
Impakt faktor: 6.446, rok: 2011

Blood flukes of the genus Schistosoma cause the disease schistosomiasis that infects over 200 million people worldwide. Schistosoma mansoni cathepsin B1 (SmCB1) is a gut-associated protease that digests host blood proteins as source of nutrients. Enzymatic activity of the SmCB1 zymogen is prevented by the pro-peptide that sterically blocks the active site until activation of the zymogen to the mature enzyme. We investigated the structure-inhibition relationships of how the SmCB1 pro-peptide interacts with the enzyme core using a SmCB1 zymogen model and pro-peptide-derived synthetic fragments. Two regions were identified within the pro-peptide that govern its inhibitory interaction with the enzyme core: an 'active site region' and a unique 'heparin-binding region' that requires heparin. Using the active site region as a template and a docking model of SmCB1, we designed a series of inhibitors mimicking the pro-peptide structure.
Trvalý link: http://hdl.handle.net/11104/0198006