Prolyl Oligopeptidase from the Blood Fluke Schistosoma mansoni : From Functional Analysis to Anti-schistosomal Inhibitors: e0003827

Background Blood flukes of the genus Schistosoma cause schistosomiasis, a parasitic disease that infects over 240 million people worldwide, and for which there is a need to identify new targets for chemotherapeutic interventions. Our research is focused on Schistosoma mansoni prolyl oligopeptidase (...

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Veröffentlicht in:PLoS neglected tropical diseases 2015-06, Vol.9 (6)
Hauptverfasser: Fajtová, Pavla, Stefanic, Sasa, Hradilek, Martin, Dvorák, Jan, Vondrásek, Jirí, Jílková, Adéla, Ulrychová, Lenka, McKerrow, James H, Caffrey, Conor R, Mares, Michael, Horn, Martin
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container_issue 6
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container_title PLoS neglected tropical diseases
container_volume 9
creator Fajtová, Pavla
Stefanic, Sasa
Hradilek, Martin
Dvorák, Jan
Vondrásek, Jirí
Jílková, Adéla
Ulrychová, Lenka
McKerrow, James H
Caffrey, Conor R
Mares, Michael
Horn, Martin
description Background Blood flukes of the genus Schistosoma cause schistosomiasis, a parasitic disease that infects over 240 million people worldwide, and for which there is a need to identify new targets for chemotherapeutic interventions. Our research is focused on Schistosoma mansoni prolyl oligopeptidase (SmPOP) from the serine peptidase family S9, which has not been investigated in detail in trematodes. Methodology/Principal Findings We demonstrate that SmPOP is expressed in adult worms and schistosomula in an enzymatically active form. By immunofluorescence microscopy, SmPOP is localized in the tegument and parenchyma of both developmental stages. Recombinant SmPOP was produced in Escherichia coli and its active site specificity investigated using synthetic substrate and inhibitor libraries, and by homology modeling. SmPOP is a true oligopeptidase that hydrolyzes peptide (but not protein) substrates with a strict specificity for Pro at P1. The inhibition profile is analogous to those for mammalian POPs. Both the recombinant enzyme and live worms cleave host vasoregulatory, proline-containing hormones such as angiotensin I and bradykinin. Finally, we designed nanomolar inhibitors of SmPOP that induce deleterious phenotypes in cultured schistosomes. Conclusions/Significance We provide the first localization and functional analysis of SmPOP together with chemical tools for measuring its activity. We briefly discuss the notion that SmPOP, operating at the host-parasite interface to cleave host bioactive peptides, may contribute to the survival of the parasite. If substantiated, SmPOP could be a new target for the development of anti-schistosomal drugs.
doi_str_mv 10.1371/journal.pntd.0003827
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Our research is focused on Schistosoma mansoni prolyl oligopeptidase (SmPOP) from the serine peptidase family S9, which has not been investigated in detail in trematodes. Methodology/Principal Findings We demonstrate that SmPOP is expressed in adult worms and schistosomula in an enzymatically active form. By immunofluorescence microscopy, SmPOP is localized in the tegument and parenchyma of both developmental stages. Recombinant SmPOP was produced in Escherichia coli and its active site specificity investigated using synthetic substrate and inhibitor libraries, and by homology modeling. SmPOP is a true oligopeptidase that hydrolyzes peptide (but not protein) substrates with a strict specificity for Pro at P1. The inhibition profile is analogous to those for mammalian POPs. Both the recombinant enzyme and live worms cleave host vasoregulatory, proline-containing hormones such as angiotensin I and bradykinin. Finally, we designed nanomolar inhibitors of SmPOP that induce deleterious phenotypes in cultured schistosomes. Conclusions/Significance We provide the first localization and functional analysis of SmPOP together with chemical tools for measuring its activity. We briefly discuss the notion that SmPOP, operating at the host-parasite interface to cleave host bioactive peptides, may contribute to the survival of the parasite. 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subjects Blood
Drug resistance
Enzymes
Mass spectrometry
Parasites
Parasitic diseases
Peptides
Proteins
Scientific imaging
Tropical diseases
title Prolyl Oligopeptidase from the Blood Fluke Schistosoma mansoni : From Functional Analysis to Anti-schistosomal Inhibitors: e0003827
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