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Crystal structure and chemical inhibition of essential schistosome host-interactive virulence factor carbonic anhydrase SmCA

The intravascular parasitic worm Schistosoma mansoni is a causative agent of schistosomiasis, a disease of great global public health significance. Here we identify an α-carbonic anhydrase (SmCA) that is expressed at the schistosome surface as determined by activity assays and immunofluorescence/imm...

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Autores principales: Da’dara, Akram A., Angeli, Andrea, Ferraroni, Marta, Supuran, Claudiu T., Skelly, Patrick J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728359/
https://www.ncbi.nlm.nih.gov/pubmed/31508507
http://dx.doi.org/10.1038/s42003-019-0578-0
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author Da’dara, Akram A.
Angeli, Andrea
Ferraroni, Marta
Supuran, Claudiu T.
Skelly, Patrick J.
author_facet Da’dara, Akram A.
Angeli, Andrea
Ferraroni, Marta
Supuran, Claudiu T.
Skelly, Patrick J.
author_sort Da’dara, Akram A.
collection PubMed
description The intravascular parasitic worm Schistosoma mansoni is a causative agent of schistosomiasis, a disease of great global public health significance. Here we identify an α-carbonic anhydrase (SmCA) that is expressed at the schistosome surface as determined by activity assays and immunofluorescence/immunogold localization. Suppressing SmCA expression by RNAi significantly impairs the ability of larval parasites to infect mice, validating SmCA as a rational drug target. Purified, recombinant SmCA possesses extremely rapid CO(2) hydration kinetics (k(cat): 1.2 × 10(6) s(-1); k(cat)/K(m): 1.3 × 10(8) M(-1)s(-1)). The enzyme’s crystal structure was determined at 1.75 Å resolution and a collection of sulfonamides and anions were tested for their ability to impede rSmCA action. Several compounds (phenylarsonic acid, phenylbaronic acid, sulfamide) exhibited favorable K(i)s for SmCA versus two human isoforms. Such selective rSmCA inhibitors could form the basis of urgently needed new drugs that block essential schistosome metabolism, blunt parasite virulence and debilitate these important global pathogens.
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spelling pubmed-67283592019-09-10 Crystal structure and chemical inhibition of essential schistosome host-interactive virulence factor carbonic anhydrase SmCA Da’dara, Akram A. Angeli, Andrea Ferraroni, Marta Supuran, Claudiu T. Skelly, Patrick J. Commun Biol Article The intravascular parasitic worm Schistosoma mansoni is a causative agent of schistosomiasis, a disease of great global public health significance. Here we identify an α-carbonic anhydrase (SmCA) that is expressed at the schistosome surface as determined by activity assays and immunofluorescence/immunogold localization. Suppressing SmCA expression by RNAi significantly impairs the ability of larval parasites to infect mice, validating SmCA as a rational drug target. Purified, recombinant SmCA possesses extremely rapid CO(2) hydration kinetics (k(cat): 1.2 × 10(6) s(-1); k(cat)/K(m): 1.3 × 10(8) M(-1)s(-1)). The enzyme’s crystal structure was determined at 1.75 Å resolution and a collection of sulfonamides and anions were tested for their ability to impede rSmCA action. Several compounds (phenylarsonic acid, phenylbaronic acid, sulfamide) exhibited favorable K(i)s for SmCA versus two human isoforms. Such selective rSmCA inhibitors could form the basis of urgently needed new drugs that block essential schistosome metabolism, blunt parasite virulence and debilitate these important global pathogens. Nature Publishing Group UK 2019-09-05 /pmc/articles/PMC6728359/ /pubmed/31508507 http://dx.doi.org/10.1038/s42003-019-0578-0 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Da’dara, Akram A.
Angeli, Andrea
Ferraroni, Marta
Supuran, Claudiu T.
Skelly, Patrick J.
Crystal structure and chemical inhibition of essential schistosome host-interactive virulence factor carbonic anhydrase SmCA
title Crystal structure and chemical inhibition of essential schistosome host-interactive virulence factor carbonic anhydrase SmCA
title_full Crystal structure and chemical inhibition of essential schistosome host-interactive virulence factor carbonic anhydrase SmCA
title_fullStr Crystal structure and chemical inhibition of essential schistosome host-interactive virulence factor carbonic anhydrase SmCA
title_full_unstemmed Crystal structure and chemical inhibition of essential schistosome host-interactive virulence factor carbonic anhydrase SmCA
title_short Crystal structure and chemical inhibition of essential schistosome host-interactive virulence factor carbonic anhydrase SmCA
title_sort crystal structure and chemical inhibition of essential schistosome host-interactive virulence factor carbonic anhydrase smca
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728359/
https://www.ncbi.nlm.nih.gov/pubmed/31508507
http://dx.doi.org/10.1038/s42003-019-0578-0
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