Aromatic thioglycoside inhibitors against the virulence factor LecA from Pseudomonas aeruginosa.
Three small families of hydrolytically stable thioaryl glycosides were prepared as inhibitors of the LecA (PA-IL) virulence factor corresponding to the carbohydrate binding lectin from the bacterial pathogen Pseudomonas aeruginosa. The monosaccharidic arylthio β-d-galactopyranosides served as a common template for the major series that was also substituted at the O-3 position. Arylthio disaccharides from lactose and from melibiose constituted the other two series members. In spite of the fact that the natural ligand for LecA is a glycolipid of the globotriaosylceramide having an α-d-galactopyranoside epitope, this study illustrated that the β-d-galactopyranoside configuration having a hydrophobic aglycon could override the requirement toward the anomeric configuration of the natural sugar. The enzyme linked lectin assay together with isothermal titration microcalorimetry established that naphthyl 1-thio-β-d-galactopyranoside () gave the best inhibition with an IC50 twenty-three times better than that of the reference methyl α-d-galactopyranoside. In addition it showed a KD of 6.3 μM which was ten times better than that of the reference compound. The X-ray crystal structure of LecA with was also obtained.
PharmaQAM - Department of Chemistry, Université du Québec à Montréal, P.O. Box 8888, Succ. Centre-ville, Montréal, Québec, Canada H3C 3P8. roy.rene@uqam.ca.
Jacques
J
Rodrigue
Géraldine
G
Ganne
Bertrand
B
Blanchard
Catherine
C
Saucier
Denis
D
Giguère
Tze Chieh
TC
Shiao
Annabelle
A
Varrot
Anne
A
Imberty
René
R
Roy
D018829:Adhesins, Bacterial / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013865:Thioglycosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D018829:Adhesins, Bacterial; C102929:LecA protein, bacteria; D013865:Thioglycosides