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Titolo:
Synthesis and structure-activity relationships of di- and trisaccharide inhibitors for Shiga-like toxin Type 1
Autore:
Kitov, PI; Bundle, DR;
Indirizzi:
Univ Alberta, Dept Chem, Edmonton, AB T6G 2G2, Canada Univ Alberta Edmonton AB Canada T6G 2G2 hem, Edmonton, AB T6G 2G2, Canada
Titolo Testata:
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1
fascicolo: 8, , anno: 2001,
pagine: 838 - 853
SICI:
1472-7781(2001):8<838:SASROD>2.0.ZU;2-E
Fonte:
ISI
Lingua:
ENG
Soggetto:
ESCHERICHIA-COLI; GLOBOTRIAOSYL CERAMIDE; CARBOHYDRATE RECEPTOR; BINDING-SITES; B-SUBUNIT; IDENTIFICATION; DERIVATIVES; GLYCOSIDES; ANALOGS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Physical, Chemical & Earth Sciences
Citazioni:
29
Recensione:
Indirizzi per estratti:
Indirizzo: Bundle, DR Univ Alberta, Dept Chem, Edmonton, AB T6G 2G2, Canada Univ Alberta Edmonton AB Canada T6G 2G2 on, AB T6G 2G2, Canada
Citazione:
P.I. Kitov e D.R. Bundle, "Synthesis and structure-activity relationships of di- and trisaccharide inhibitors for Shiga-like toxin Type 1", J CHEM S P1, (8), 2001, pp. 838-853

Abstract

The syntheses of galabiose and P-k-trisaccharide analogues in which selected hydroxy groups are replaced by O-methyl, amino deoxy, acetamido deoxy, and carboxyalkyl groups are reported. The ability of these inhibitors to block E. coli verotoxin 1 binding to its mammalian cell-surface receptor are evaluated by a solid-phase competition assay. The synthesis of a biotinylated glycoconjugate for this assay is described, wherein a P-k-trisaccharide tether derivative 70 is constructed and covalently attached to bovine serum albumin followed by biotinylation. Galabiose derivatives 4 and 5 that contain a carboxymethyl or carboxyethyl substituent at O-2 of the beta -galactose residue show 15-20-fold activity gains over the methyl glycoside of galabiose. This enhanced activity is not observed for the corresponding carboxymethyl-substituted P-k-trisaccharide analogue 13. The inhibition data are rationalized with the solved crystal structure for verotoxin 1 complexed witha P-k-trisaccharide analogue and provide insight for the design of dimericinhibitors that can exploit the unique binding-site distribution of the toxin's B subunit. This discussion provides a further example of the important role played by ordered water molecules in sugar-protein complexes.

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Documento generato il 18/01/20 alle ore 10:43:04