1. Lactose derivatives are inhibitors of Trypanosoma cruzi trans-sialidase activity toward conventional substrates in vitro and in vivo
- Author
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Alberto C.C. Frasch, Rosalía Agusti, Gastón Paris, Rosa M. de Lederkremer, and Laura Ratier
- Subjects
anion exchange chromatography ,Glycoconjugate ,Biochemistry ,Substrate Specificity ,chemistry.chemical_compound ,Sugar Alcohols ,Chlorocebus aethiops ,Alternative substrates ,amperometry ,n acetyllactosamine ,Enzyme Inhibitors ,Lactose ,enzyme inhibition ,chemistry.chemical_classification ,Virulence ,HPAEC ,sialidase ,article ,parasite virulence ,unclassified drug ,enzyme activity ,aminosugar ,priority journal ,Mammalia ,carbohydrate derivative ,Protein Binding ,Trypanosoma ,in vitro study ,Lactitol ,Trans-sialidase ,Trypanosoma cruzi ,enzyme inhibitor ,lactitol ,alkalinity ,Neuraminidase ,Biology ,Sialidase ,lactose derivative ,Cercopithecus aethiops ,Microbiology ,lactose ,in vivo study ,carbohydrate analysis ,Animals ,controlled study ,Chagas Disease ,3 o beta dextro galactopyranosylarabinopyranose ,human ,enzyme specificity ,3 o beta dextro galactopyranosylarabinofuranone ,Vero Cells ,enzyme substrate ,Glycoproteins ,Binding Sites ,Inhibitors ,binding site ,Vero cell ,human cell ,lactobionic acid ,Lactose binding ,biology.organism_classification ,Lactobionic acid ,Protein Structure, Tertiary ,Sialic acid ,3 o beta dextro galactopyranosylarabinitol ,drug efficacy ,drug structure ,chemistry ,concentration response ,Sialic Acids ,5 (3' o beta dextro galactopyranosylglucopentitol 1' yl)tetrazole - Abstract
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.
- Published
- 2004