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

GIORGI, M. EUGENIA; RATIER, LAURA; AGUSTI, ROSALÍA; FRASCH, ALBERTO; MUCHNIK DE LEDERKREMER, R

GLYCOBIOLOGY

OXFORD UNIV PRESS INC

Lugar: Oxford; Año: 2012 vol. 22 p. 1363 - 1373

0959-6658

The trans-sialidase of Trypanosoma cruzi (TcTS) catalizes the transfer of sialic acid from host glycoconjugates to terminal b-galactopyranosides in the mucins of the parasite. The enzyme is shed to the medium and may affect the immune system of the host. We have previously described that lactose derivatives effectively inhibited the transfer of sialic acid to N-acetyllactosamine. Lactitol also prevented the apoptosis caused by the TcTS, although it is rapidly eliminated from the circulatory system. In this paper we report the covalent conjugation of eight arm polyethyleneglycol (PEG) with lactose analogs. Two approaches were used for PEGylation of disaccharide derivatives containing b-D-Galp as non-reducing unit. 1. Amide formation between benzyl b-D-galactopyranosyl-(1®6)-2-amino-2-deoxy-a-D-glucopyranoside and a succinimide activated PEG. 2. Conjugation of lactobionolactone with amino end-functionalized PEG. Two 8-arm PEG derivatives (20 kDa and 40 kDa) were used for each sugar. Substitution of all arms was proven by 1H NMR spectroscopy. The bioavailability of the conjugates in mice plasma was considerably improved with respect to the 5 kDa linear PEG conjugates though retaining their inhibitory properties.