title: 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).
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht University P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
authors.forename: Ou
authors.initials: O
authors.lastname: Fu
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht University P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
authors.forename: Aliaksei V
authors.initials: AV
authors.lastname: Pukin
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht University P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
authors.forename: H C
authors.initials: HC
authors.lastname: Quarles van Ufford
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht University P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Kemmink
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht University P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
authors.forename: Nico J
authors.initials: NJ
authors.lastname: de Mol
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht University P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
authors.forename: Roland J
authors.initials: RJ
authors.lastname: Pieters
keywords: LecA inhibition; bacterial lectins; carbohydrates; molecular modeling; multivalency; virulence factors