Mapping the pro-peptide of the Schistosoma mansoni cathepsin B1 drug target: modulation of inhibition by heparin and design of mimetic inhibitors
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
21375333
DOI
10.1021/cb100411v
Knihovny.cz E-resources
- MeSH
- Chromatography, Affinity MeSH
- Heparin pharmacology MeSH
- Protein Kinase Inhibitors chemical synthesis chemistry pharmacology MeSH
- Catalytic Domain drug effects MeSH
- Cathepsin B antagonists & inhibitors metabolism MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Peptide Mapping * MeSH
- Peptides chemistry pharmacology MeSH
- Swine MeSH
- Drug Design * MeSH
- Schistosoma mansoni enzymology MeSH
- Protein Structure, Secondary MeSH
- Intestinal Mucosa chemistry MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Heparin MeSH
- Protein Kinase Inhibitors MeSH
- Cathepsin B MeSH
- Peptides MeSH
Blood flukes of the genus Schistosoma cause the disease schistosomiasis that infects over 200 million people worldwide. Treatment relies on just one drug, and new therapies are needed should drug resistance emerge. Schistosoma mansoni cathepsin B1 (SmCB1) is a gut-associated protease that digests host blood proteins as source of nutrients. It is under evaluation as a therapeutic target. 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. The latter region is apparently only found in the pro-peptides of cathepsins B associated with the gut of trematode parasites. Finally, 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, the best of which yielded low micromolar inhibition constants. Overall, we identify a novel glycosaminoglycan-mediated mechanism of inhibition by the pro-peptide that potentially regulates zymogen activation and describe a promising design strategy to develop antischistosomal drugs.
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