Lactose derivatives are inhibitors of Trypanosoma cruzi trans-sialidase activity toward conventional substrates in vitro and in vivo

被引:61
作者
Agustí, R
París, G
Ratier, L
Frasch, ACC
de Lederkremer, RM
机构
[1] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Quim Organ, CIHIDECAR, RA-1428 Buenos Aires, DF, Argentina
[2] Univ Nacl Gen San Martin, Inst Tecnol Chascomus, Inst Invest Biotecnol, RA-1650 Gen San Martin, Argentina
[3] INTI, Consejo Nacl Invest Cient & Tecn, RA-1650 Gen San Martin, Argentina
关键词
alternative substrates; HPAEC; inhibitors; trans-sialidase; Trypanosoma cruzi;
D O I
10.1093/glycob/cwh079
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 beta-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.
引用
收藏
页码:659 / 670
页数:12
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