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

Publication at Faculty of Science |
2011

Abstract

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.