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Abstract:

The trans-sialidase of Trypanosoma cruzi (TcTS) catalyzes the transfer of sialic acid from host glycoconjugates to terminal β-galactopyranosides in the mucins of the parasite. During infection, the enzyme is actively shed by the parasite to the bloodstream inducing hematological alterations. Lactitol prevents cell apoptosis caused by the TcTS, although it is rapidly eliminated from the circulatory system. Linear polyethyleneglycol (PEG) conjugates of lactose analogs were prepared but their clearance from blood was still quite fast. With the aim of improving their circulating half-lives in vivo, we now synthesized covalent conjugates of eight-arm PEG. The star-shape of these conjugates allows an increase in the molecular weight together with the loading of the active sugar. Two approaches were used for PEGylation of disaccharide derivatives containing β-d-Galp as the non-reducing unit. (1) Amide formation between benzyl-d-galactopyranosyl-(1→6)-2-amino-2-deoxy α-d-glucopyranoside and a succinimide-activated PEG. (2) Conjugation of lactobionolactone with amino end-functionalized PEG. Two 8-arm PEG derivatives (20 and 40 kDa) were used for each sugar. Substitution of all arms was proved by 1H nuclear magnetic resonance (NMR) spectroscopy. The bioavailability of the conjugates in mice plasma was considerably improved with respect to the 5 kDa linear PEG conjugates retaining their inhibitory properties. © 2012 The Author.

Registro:

Documento: Artículo
Título:Improved bioavailability of inhibitors of Trypanosoma cruzi trans-sialidase: PEGylation of lactose analogs with multiarm polyethyleneglycol
Autor:Giorgi, M.E.; Ratier, L.; Agusti, R.; Frasch, A.C.C.; De Lederkremer, R.M.
Filiación:Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Buenos Aires, Argentina
Univ. Nacional de General San Martin y Consejo Nacional de Investigaciones Cientificas y Tecnicas, INTI, Av. General Paz 5445, Edificio 24, Casilla de correo 30, 1650 General San Martín, Argentina
Palabras clave:inhibitors; multiarm conjugates; PEGylation; trans-sialidase; Trypanosoma cruzi; disaccharide; lactose; macrogol; sialidase; animal experiment; animal model; apoptosis; article; bioavailability; cardiovascular system; controlled study; in vivo study; infection; molecular weight; mouse; nonhuman; nuclear magnetic resonance spectroscopy; parasite; plasma clearance; priority journal; Trypanosoma cruzi; Biological Availability; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glycoproteins; Lactose; Magnetic Resonance Spectroscopy; Molecular Structure; Neuraminidase; Polyethylene Glycols; Structure-Activity Relationship; Trypanosoma cruzi; Mus; Trypanosoma cruzi
Año:2012
Volumen:22
Número:10
Página de inicio:1363
Página de fin:1373
DOI: http://dx.doi.org/10.1093/glycob/cws091
Título revista:Glycobiology
Título revista abreviado:Glycobiology
ISSN:09596658
CODEN:GLYCE
CAS:lactose, 10039-26-6, 16984-38-6, 63-42-3, 64044-51-5; macrogol, 25322-68-3; sialidase, 9001-67-6; Enzyme Inhibitors; Glycoproteins; Lactose, J2B2A4N98G; Neuraminidase, 3.2.1.18; Polyethylene Glycols; trans-sialidase, 3.2.1.-
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09596658_v22_n10_p1363_Giorgi

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Citas:

---------- APA ----------
Giorgi, M.E., Ratier, L., Agusti, R., Frasch, A.C.C. & De Lederkremer, R.M. (2012) . Improved bioavailability of inhibitors of Trypanosoma cruzi trans-sialidase: PEGylation of lactose analogs with multiarm polyethyleneglycol. Glycobiology, 22(10), 1363-1373.
http://dx.doi.org/10.1093/glycob/cws091
---------- CHICAGO ----------
Giorgi, M.E., Ratier, L., Agusti, R., Frasch, A.C.C., De Lederkremer, R.M. "Improved bioavailability of inhibitors of Trypanosoma cruzi trans-sialidase: PEGylation of lactose analogs with multiarm polyethyleneglycol" . Glycobiology 22, no. 10 (2012) : 1363-1373.
http://dx.doi.org/10.1093/glycob/cws091
---------- MLA ----------
Giorgi, M.E., Ratier, L., Agusti, R., Frasch, A.C.C., De Lederkremer, R.M. "Improved bioavailability of inhibitors of Trypanosoma cruzi trans-sialidase: PEGylation of lactose analogs with multiarm polyethyleneglycol" . Glycobiology, vol. 22, no. 10, 2012, pp. 1363-1373.
http://dx.doi.org/10.1093/glycob/cws091
---------- VANCOUVER ----------
Giorgi, M.E., Ratier, L., Agusti, R., Frasch, A.C.C., De Lederkremer, R.M. Improved bioavailability of inhibitors of Trypanosoma cruzi trans-sialidase: PEGylation of lactose analogs with multiarm polyethyleneglycol. Glycobiology. 2012;22(10):1363-1373.
http://dx.doi.org/10.1093/glycob/cws091