Functionalization of a Rigid Divalent Ligand for LecA, a Bacterial Adhesion Lectin

Abstract

The bacterial adhesion lectin LecA is an attractive target for interference with the infectivity of its producer P.aeruginosa. Divalent ligands with two terminal galactoside moieties connected by an alternating glucose-triazole spacer were previously shown to be very potent inhibitors. In this study, we chose to prepare a series of derivatives with various new substituents in the spacer in hopes of further enhancing the LecA inhibitory potency of the molecules. Based on the binding mode, modifications were made to the spacer to enable additional spacer-protein interactions. The introduction of positively charged, negatively charged, and also lipophilic functional groups was successful. The compounds were good LecA ligands, but no improved binding was seen, even though altered thermodynamic parameters were observed by isothermal titration calorimetry (ITC). Linkers for lectin ligands! The P.aeruginosa lectin and virulence factor LecA can be efficiently blocked by divalent galactoside ligands containing a rigid spacer. Further functionalization of the spacer was explored in order to foster spacer-protein interactions. Positively and negatively charged groups as well as lipophilic groups were used for this purpose.