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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.

Registro:

Documento: Artículo
Título:Lactose derivatives are inhibitors of Trypanosoma cruzi trans-sialidase activity toward conventional substrates in vitro and in vivo
Autor:Agustí, R.; París, G.; Ratier, L.; Frasch, A.C.C.; de Lederkremer, R.M.
Filiación:CIHIDECAR, Departamento de Quimica Organica, Fac. de Ciencias Exactas y Naturales, Pabellón II, 1428 Buenos Aires, Argentina
Inst. de Invest. Biotechnologicas, Univ. Nacional de Gen. San Martin, INTI, Av. General Paz s/n, Edificio 24, 1650 General San Martín, Argentina
Palabras clave: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
Año:2004
Volumen:14
Número:7
Página de inicio:659
Página de fin:670
DOI: http://dx.doi.org/10.1093/glycob/cwh079
Handle:http://hdl.handle.net/20.500.12110/paper_09596658_v14_n7_p659_Agusti
Título revista:Glycobiology
Título revista abreviado:Glycobiology
ISSN:09596658
CODEN:GLYCE
CAS:lactitol, 585-86-4; lactobionic acid, 96-82-2; lactose, 10039-26-6, 16984-38-6, 63-42-3, 64044-51-5; sialidase, 9001-67-6; Enzyme Inhibitors; Glycoproteins; lactitol, 585-86-4; Neuraminidase, EC 3.2.1.18; Sialic Acids; Sugar Alcohols; trans-sialidase, EC 3.2.1.-
PDF:https://bibliotecadigital.exactas.uba.ar/download/paper/paper_09596658_v14_n7_p659_Agusti.pdf
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09596658_v14_n7_p659_Agusti

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Citas:

---------- APA ----------
Agustí, R., París, G., Ratier, L., Frasch, A.C.C. & de Lederkremer, R.M. (2004) . Lactose derivatives are inhibitors of Trypanosoma cruzi trans-sialidase activity toward conventional substrates in vitro and in vivo. Glycobiology, 14(7), 659-670.
http://dx.doi.org/10.1093/glycob/cwh079
---------- CHICAGO ----------
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" . Glycobiology 14, no. 7 (2004) : 659-670.
http://dx.doi.org/10.1093/glycob/cwh079
---------- MLA ----------
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" . Glycobiology, vol. 14, no. 7, 2004, pp. 659-670.
http://dx.doi.org/10.1093/glycob/cwh079
---------- VANCOUVER ----------
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. Glycobiology. 2004;14(7):659-670.
http://dx.doi.org/10.1093/glycob/cwh079