Improved bioavailability of inhibitors of Trypanosoma cruzi trans-sialidase: PEGylation of lactose analogs with multiarm polyethyleneglycol

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. Lactito...

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Autores principales:	Giorgi, M.E., Ratier, L., Agusti, R., Frasch, A.C.C., De Lederkremer, R.M.
Formato:	JOUR
Materias:	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 Biological Availability Dose-Response Relationship, Drug Enzyme Inhibitors Glycoproteins Lactose Magnetic Resonance Spectroscopy Molecular Structure Neuraminidase Polyethylene Glycols Structure-Activity Relationship Mus
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_09596658_v22_n10_p1363_Giorgi
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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spelling	todo:paper_09596658_v22_n10_p1363_Giorgi2023-10-03T15:53:04Z Improved bioavailability of inhibitors of Trypanosoma cruzi trans-sialidase: PEGylation of lactose analogs with multiarm polyethyleneglycol Giorgi, M.E. Ratier, L. Agusti, R. Frasch, A.C.C. De Lederkremer, R.M. 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 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. Fil:Giorgi, M.E. 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:Agusti, R. 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_v22_n10_p1363_Giorgi
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	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
spellingShingle	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 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
topic_facet	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
description	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.
format	JOUR
author	Giorgi, M.E. Ratier, L. Agusti, R. Frasch, A.C.C. De Lederkremer, R.M.
author_facet	Giorgi, M.E. Ratier, L. Agusti, R. Frasch, A.C.C. De Lederkremer, R.M.
author_sort	Giorgi, M.E.
title	Improved bioavailability of inhibitors of Trypanosoma cruzi trans-sialidase: PEGylation of lactose analogs with multiarm polyethyleneglycol
title_short	Improved bioavailability of inhibitors of Trypanosoma cruzi trans-sialidase: PEGylation of lactose analogs with multiarm polyethyleneglycol
title_full	Improved bioavailability of inhibitors of Trypanosoma cruzi trans-sialidase: PEGylation of lactose analogs with multiarm polyethyleneglycol
title_fullStr	Improved bioavailability of inhibitors of Trypanosoma cruzi trans-sialidase: PEGylation of lactose analogs with multiarm polyethyleneglycol
title_full_unstemmed	Improved bioavailability of inhibitors of Trypanosoma cruzi trans-sialidase: PEGylation of lactose analogs with multiarm polyethyleneglycol
title_sort	improved bioavailability of inhibitors of trypanosoma cruzi trans-sialidase: pegylation of lactose analogs with multiarm polyethyleneglycol
url	http://hdl.handle.net/20.500.12110/paper_09596658_v22_n10_p1363_Giorgi
work_keys_str_mv	AT giorgime improvedbioavailabilityofinhibitorsoftrypanosomacruzitranssialidasepegylationoflactoseanalogswithmultiarmpolyethyleneglycol AT ratierl improvedbioavailabilityofinhibitorsoftrypanosomacruzitranssialidasepegylationoflactoseanalogswithmultiarmpolyethyleneglycol AT agustir improvedbioavailabilityofinhibitorsoftrypanosomacruzitranssialidasepegylationoflactoseanalogswithmultiarmpolyethyleneglycol AT fraschacc improvedbioavailabilityofinhibitorsoftrypanosomacruzitranssialidasepegylationoflactoseanalogswithmultiarmpolyethyleneglycol AT delederkremerrm improvedbioavailabilityofinhibitorsoftrypanosomacruzitranssialidasepegylationoflactoseanalogswithmultiarmpolyethyleneglycol
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Improved bioavailability of inhibitors of Trypanosoma cruzi trans-sialidase: PEGylation of lactose analogs with multiarm polyethyleneglycol

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