Synthesis of multivalent Streptococcus suis adhesion inhibitors by enzymatic cleavage of polygalacturonic acid and 'click' conjugation.
A galabiose disaccharide building block was synthesized by an efficient pectinase cleavage of polygalacturonic acid and subsequent chemical functional group transformations. Besides the disaccharide, the corresponding trisaccharide was also obtained and modified. The compounds were subsequently conjugated to dendrimers with up to eight end groups using 'click' chemistry. The compounds were evaluated as inhibitors of adhesion of the pathogen Streptococcus suis in a hemagglutination assay and strong inhibition was observed for the tetra- and octavalent galabiose compound with MIC values in the low nanomolar range. The corresponding octavalent trisaccharide was a ca. 20-fold weaker inhibitor.
Branderhorst
Hilbert M
HM
Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands.
Kooij
Raymond
R
Salminen
Annika
A
Jongeneel
Lieneke H
LH
Arnusch
Christopher J
CJ
Liskamp
Rob M J
RM
Finne
Jukka
J
Pieters
Roland J
RJ
D002240:Carbohydrate Sequence; D002448:Cell Adhesion / Q000187:drug effects; D050091:Dendrimers / Q000737:chemistry; D004187:Disaccharides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006385:Hemagglutination Inhibition Tests; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010368:Pectins / Q000737:chemistry*; D011096:Polygalacturonase / Q000737:chemistry*; D012680:Sensitivity and Specificity; D017011:Streptococcus suis / Q000187:drug effects* / Q000472:pathogenicity
D050091:Dendrimers; D004187:Disaccharides; C032103:4-O-alpha-D-galactopyranosyl-D-galactose; D010368:Pectins; D011096:Polygalacturonase; C003181:polygalacturonic acid