Synthesis of PEGylated lactose analogs for inhibition studies on T.cruzi trans-sialidase

Giorgi, M. Eugenia; Ratier, Laura; Agusti, Rosalía; Frasch, Alberto C.C.; Lederkremer, Rosa M. de

doi:10.1007/s10719-010-9300-7

Cited by 21 publications

(15 citation statements)

References 39 publications

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“…Thus, TcTS increases the pathogenicity and virulence of the parasite (Fig. 3B) (Harper et al, 2004;Giorgi et al, 2010). R. prolixus is the main vector of Chagas disease caused by T. cruzi in Central America and its midgut digestive enzymes play a critical role in the survival and infection of T. cruzi (Lopez-Ordonez, Rodriguez & Hernandez-Hernandez, 2001).…”

Section: (4) Parasitesmentioning

confidence: 99%

Glycosaminoglycans in infectious disease

et al. 2013

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Glycosaminoglycans (GAGs) are complex carbohydrates that are ubiquitously present on the cell surface and in the extracellular matrix. Interactions between GAGs and pathogens represent the first line of contact between pathogen and host cell and are crucial to a pathogen's invasive potential. Their complexity and structural diversity allow GAGs to control a wide array of biological interactions influencing many physiological and pathological processes, including adhesion, cell-to-cell communication, biochemical cascades, and the immune response. In recent years, increasing evidence indicates an extraordinary role for GAGs in the pathogenesis of viruses, bacteria and parasites. Herein, we examine the interface between GAGs and different pathogens, and address the divergent biological functions of GAGs in infectious disease. We consider approaches to use this understanding to design novel therapeutic strategies addressing new challenges in the treatment of infectious diseases.

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Section: (4) Parasitesmentioning

confidence: 99%

Glycosaminoglycans in infectious disease

et al. 2013

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“…Instead, the parasite expresses trans-sialidase (TS), which mediates transfer of sialic acid from host glycoconjugates to parasite mucins [18]–[20]. T. cruzi TS depletes platelets with sialic acid, increasing clearance and leading to thrombocytopenia during acute infection [21].…”

Section: Introductionmentioning

confidence: 99%

Oral Exposure to Phytomonas serpens Attenuates Thrombocytopenia and Leukopenia during Acute Infection with Trypanosoma cruzi

et al. 2013

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Mice infected with Trypanosoma cruzi, the agent of Chagas disease, rapidly develop anemia and thrombocytopenia. These effects are partially promoted by the parasite trans-sialidase (TS), which is shed in the blood and depletes sialic acid from the platelets, inducing accelerated platelet clearance and causing thrombocytopenia during the acute phase of disease. Here, we demonstrate that oral immunization of C57BL/6 mice with Phytomonas serpens, a phytoflagellate parasite that shares common antigens with T. cruzi but has no TS activity, reduces parasite burden and prevents thrombocytopenia and leukopenia. Immunization also reduces platelet loss after intraperitoneal injection of TS. In addition, passive transfer of immune sera raised in mice against P. serpens prevented platelet clearance. Thus, oral exposure to P. serpens attenuates the progression of thrombocytopenia induced by TS from T. cruzi. These findings are not only important for the understanding of the pathogenesis of T. cruzi infection but also for developing novel approaches of intervention in Chagas disease.

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“…Accordingly, it was shown that the methyl glycoside of β-D-Galp(1→6)-D-Galp is even a better substrate than lactose in the TcTS reaction (Harrison et al 2011). Compound 1, prepared as previously described (Giorgi et al 2010), was conjugated by amidation of the 2-amino group with 8-arm PEGs constructed on a hexaglycerin core and activated as N-succinimide succinate (SSPEG) (Scheme 1). Two commercial SSPEG with molecular weights of 20 204 and 42 680 Da, according to the certificate of analysis of the manufacturer, were used.…”

Section: Synthesis Of Multiarm Peg Conjugatesmentioning

confidence: 99%

“…A recent paper describes the enzymatic copolymerization of monosaccharide acetal derivatives with PEG-600 dimethyl ester (Bhatia et al 2011). We have previously reported the preparation and characterization of linear PEG conjugates of lactose analogs for inhibition studies on TcTS (Giorgi et al 2010). Although the conjugates showed inhibition values similar to those of the precursor disaccharide, the stability in circulation was not improved, probably due to the low molecular weight of the polymer used.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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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 β-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 (1)H 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.

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Synthesis of PEGylated lactose analogs for inhibition studies on T.cruzi trans-sialidase

Cited by 21 publications

References 39 publications

Glycosaminoglycans in infectious disease

Glycosaminoglycans in infectious disease

Oral Exposure to Phytomonas serpens Attenuates Thrombocytopenia and Leukopenia during Acute Infection with Trypanosoma cruzi

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

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