Lactose derivatives are inhibitors of Trypanosoma cruzi trans-sialidase activity toward conventional substrates in vitro and in vivo
Chagas' disease, caused by Trypanosoma cruzi, affects about 18 million people in Latin America, and no effective treatment is available to date. To acquire sialic acid from the host glycoconjugates, T. cruzi expresses an unusual surface sialidase with trans-sialidase activity (TcTS) that transf...
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todo:paper_09596658_v14_n7_p659_Agusti2023-10-03T15:53:03Z Lactose derivatives are inhibitors of Trypanosoma cruzi trans-sialidase activity toward conventional substrates in vitro and in vivo Agustí, R. París, G. Ratier, L. Frasch, A.C.C. de Lederkremer, R.M. Alternative substrates HPAEC Inhibitors Trans-sialidase Trypanosoma cruzi 3 o beta dextro galactopyranosylarabinitol 3 o beta dextro galactopyranosylarabinofuranone 3 o beta dextro galactopyranosylarabinopyranose 5 (3' o beta dextro galactopyranosylglucopentitol 1' yl)tetrazole aminosugar carbohydrate derivative enzyme inhibitor lactitol lactobionic acid lactose lactose derivative n acetyllactosamine sialidase unclassified drug alkalinity amperometry anion exchange chromatography article binding site carbohydrate analysis concentration response controlled study drug efficacy drug structure enzyme activity enzyme inhibition enzyme specificity enzyme substrate human human cell in vitro study in vivo study parasite virulence priority journal Trypanosoma cruzi Vero cell Animals Binding Sites Cercopithecus aethiops Chagas Disease Enzyme Inhibitors Glycoproteins Neuraminidase Protein Binding Protein Structure, Tertiary Sialic Acids Substrate Specificity Sugar Alcohols Trypanosoma cruzi Vero Cells Virulence Mammalia Trypanosoma Trypanosoma cruzi Chagas' disease, caused by Trypanosoma cruzi, affects about 18 million people in Latin America, and no effective treatment is available to date. To acquire sialic acid from the host glycoconjugates, T. cruzi expresses an unusual surface sialidase with trans-sialidase activity (TcTS) that transfers the sugar to parasite mucins. Surface sialic acid was shown to have relevant functions in protection of the parasite against the lysis by complement and in mammalian host cell invasion. The recently determined 3D structure of TcTS allowed a detailed analysis of its catalytic site and showed the presence of a lactose-binding site where the β-linked galactose accepting the sialic acid is placed. In this article, the acceptor substrate specificity of lactose derivatives was studied by high pH anion-exchange chromatography with pulse amperometric detection. The lactose open chain derivatives lactitol and lactobionic acid, as well as other derivatives, were found to be good acceptors of sialic acid. Lactitol, which was the best of the ones tested, effectively inhibited the transfer of sialic acid to N-acetyllactosamine. Furthermore, lactitol inhibited parasite mucins re-sialylation when incubated with live trypanosomes and TcTS. Lactitol also diminished the T. cruzi infection in cultured Vero cells by 20-27%. These results indicate that compounds directed to the lactose binding site might be good inhibitors of TcTS. © Oxford University Press 2004; all rights reserved. Fil:Agustí, R. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Ratier, L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:de Lederkremer, R.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_09596658_v14_n7_p659_Agusti |
institution |
Universidad de Buenos Aires |
institution_str |
I-28 |
repository_str |
R-134 |
collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
topic |
Alternative substrates HPAEC Inhibitors Trans-sialidase Trypanosoma cruzi 3 o beta dextro galactopyranosylarabinitol 3 o beta dextro galactopyranosylarabinofuranone 3 o beta dextro galactopyranosylarabinopyranose 5 (3' o beta dextro galactopyranosylglucopentitol 1' yl)tetrazole aminosugar carbohydrate derivative enzyme inhibitor lactitol lactobionic acid lactose lactose derivative n acetyllactosamine sialidase unclassified drug alkalinity amperometry anion exchange chromatography article binding site carbohydrate analysis concentration response controlled study drug efficacy drug structure enzyme activity enzyme inhibition enzyme specificity enzyme substrate human human cell in vitro study in vivo study parasite virulence priority journal Trypanosoma cruzi Vero cell Animals Binding Sites Cercopithecus aethiops Chagas Disease Enzyme Inhibitors Glycoproteins Neuraminidase Protein Binding Protein Structure, Tertiary Sialic Acids Substrate Specificity Sugar Alcohols Trypanosoma cruzi Vero Cells Virulence Mammalia Trypanosoma Trypanosoma cruzi |
spellingShingle |
Alternative substrates HPAEC Inhibitors Trans-sialidase Trypanosoma cruzi 3 o beta dextro galactopyranosylarabinitol 3 o beta dextro galactopyranosylarabinofuranone 3 o beta dextro galactopyranosylarabinopyranose 5 (3' o beta dextro galactopyranosylglucopentitol 1' yl)tetrazole aminosugar carbohydrate derivative enzyme inhibitor lactitol lactobionic acid lactose lactose derivative n acetyllactosamine sialidase unclassified drug alkalinity amperometry anion exchange chromatography article binding site carbohydrate analysis concentration response controlled study drug efficacy drug structure enzyme activity enzyme inhibition enzyme specificity enzyme substrate human human cell in vitro study in vivo study parasite virulence priority journal Trypanosoma cruzi Vero cell Animals Binding Sites Cercopithecus aethiops Chagas Disease Enzyme Inhibitors Glycoproteins Neuraminidase Protein Binding Protein Structure, Tertiary Sialic Acids Substrate Specificity Sugar Alcohols Trypanosoma cruzi Vero Cells Virulence Mammalia Trypanosoma Trypanosoma cruzi Agustí, R. París, G. Ratier, L. Frasch, A.C.C. de Lederkremer, R.M. Lactose derivatives are inhibitors of Trypanosoma cruzi trans-sialidase activity toward conventional substrates in vitro and in vivo |
topic_facet |
Alternative substrates HPAEC Inhibitors Trans-sialidase Trypanosoma cruzi 3 o beta dextro galactopyranosylarabinitol 3 o beta dextro galactopyranosylarabinofuranone 3 o beta dextro galactopyranosylarabinopyranose 5 (3' o beta dextro galactopyranosylglucopentitol 1' yl)tetrazole aminosugar carbohydrate derivative enzyme inhibitor lactitol lactobionic acid lactose lactose derivative n acetyllactosamine sialidase unclassified drug alkalinity amperometry anion exchange chromatography article binding site carbohydrate analysis concentration response controlled study drug efficacy drug structure enzyme activity enzyme inhibition enzyme specificity enzyme substrate human human cell in vitro study in vivo study parasite virulence priority journal Trypanosoma cruzi Vero cell Animals Binding Sites Cercopithecus aethiops Chagas Disease Enzyme Inhibitors Glycoproteins Neuraminidase Protein Binding Protein Structure, Tertiary Sialic Acids Substrate Specificity Sugar Alcohols Trypanosoma cruzi Vero Cells Virulence Mammalia Trypanosoma Trypanosoma cruzi |
description |
Chagas' disease, caused by Trypanosoma cruzi, affects about 18 million people in Latin America, and no effective treatment is available to date. To acquire sialic acid from the host glycoconjugates, T. cruzi expresses an unusual surface sialidase with trans-sialidase activity (TcTS) that transfers the sugar to parasite mucins. Surface sialic acid was shown to have relevant functions in protection of the parasite against the lysis by complement and in mammalian host cell invasion. The recently determined 3D structure of TcTS allowed a detailed analysis of its catalytic site and showed the presence of a lactose-binding site where the β-linked galactose accepting the sialic acid is placed. In this article, the acceptor substrate specificity of lactose derivatives was studied by high pH anion-exchange chromatography with pulse amperometric detection. The lactose open chain derivatives lactitol and lactobionic acid, as well as other derivatives, were found to be good acceptors of sialic acid. Lactitol, which was the best of the ones tested, effectively inhibited the transfer of sialic acid to N-acetyllactosamine. Furthermore, lactitol inhibited parasite mucins re-sialylation when incubated with live trypanosomes and TcTS. Lactitol also diminished the T. cruzi infection in cultured Vero cells by 20-27%. These results indicate that compounds directed to the lactose binding site might be good inhibitors of TcTS. © Oxford University Press 2004; all rights reserved. |
format |
JOUR |
author |
Agustí, R. París, G. Ratier, L. Frasch, A.C.C. de Lederkremer, R.M. |
author_facet |
Agustí, R. París, G. Ratier, L. Frasch, A.C.C. de Lederkremer, R.M. |
author_sort |
Agustí, R. |
title |
Lactose derivatives are inhibitors of Trypanosoma cruzi trans-sialidase activity toward conventional substrates in vitro and in vivo |
title_short |
Lactose derivatives are inhibitors of Trypanosoma cruzi trans-sialidase activity toward conventional substrates in vitro and in vivo |
title_full |
Lactose derivatives are inhibitors of Trypanosoma cruzi trans-sialidase activity toward conventional substrates in vitro and in vivo |
title_fullStr |
Lactose derivatives are inhibitors of Trypanosoma cruzi trans-sialidase activity toward conventional substrates in vitro and in vivo |
title_full_unstemmed |
Lactose derivatives are inhibitors of Trypanosoma cruzi trans-sialidase activity toward conventional substrates in vitro and in vivo |
title_sort |
lactose derivatives are inhibitors of trypanosoma cruzi trans-sialidase activity toward conventional substrates in vitro and in vivo |
url |
http://hdl.handle.net/20.500.12110/paper_09596658_v14_n7_p659_Agusti |
work_keys_str_mv |
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