Medicinal Chemistry & Chemical Biology, Poster
MC-128

Dynamic cooperative glycan assembly blocks binding of bacterial lectins to epithelial cells

T. Machida1, A. Novoa1, É. Gillon 2, S. Zheng3, J. Claudinon3, T. Eierhoff3, A. Imberty2, W. Römer3, N. Winssinger1*
1Department of Organic Chemistry, NCCR Chemical Biology, University of Geneva, 30 quai Ernest Ansermet, 1211 Geneva, Switzerland, 2CERMAV UPR5301, CNRS, and Université Grenoble Alpes, BP 53, 38041 Grenoble cedex 9, France, 3Faculty of Biology, Albert-Ludwigs-University Freiburg, Schänzlestraße 1, and Centre for Biological Signalling Studies (BIOSS), Albert-Ludwigs-University Freiburg, Schänzlestraße 18, 79104 Freiburg, G

 Pathogenic bacterial infection to the host frequently utilizes lectin which recognizes glycan on cell surface of host. Lectin usually has multiple glycan-binding pockets and the multivalent inhibitor which simultaneously blocks multiple pockets is potent anti-bacterial medication strategy.  

 RSL was successfully blocked by conjugate with fucose and short peptide nucleic acid (PNA) with palindromic sequence (KD=11 nM) in which neither fucose nor PNA had comparable affinity (fucose: KD=2200 nM. PNA: GGCC, self hybridization KD=3800 nM). That suggested that host protein stabilize beneficial dimer formation. This conjugate had IC50 of 555 nM to inhibit the binding of fucose-binding lectin BambL to epithelial cells with efficiency of more than 700-hold compared to L-fucose. 

1) T. Machida, A. Novoa, É. Gillon, S. Zheng, J. Claudinon, T. Eierhoff, A. Imberty, W. Römer, N. Winssinger, Angew. Chem. Int. Ed. 2017, in press.