Development of Pseudomonas aeruginosa Lectin LecA Inhibitor by using Bivalent Galactosides Supported on Polyproline Peptide Scaffolds

Abstract

LecA is a galactose-binding tetrameric lectin from Pseudomonas aeruginosa involved in infection and biofilm formation. The emergent antibiotic resistance of P. aeruginosa has made LecA a promising pharmaceutical target to treat such infections. To develop LecA inhibitors, we exploit the unique helical structure of polyproline peptides to create a scaffold that controls the galactoside positions to fit their binding sites on LecA. With a modular scaffold design, both the galactoside ligands and the inter-ligand distance can be altered conveniently. We prepared scaffolds with spacings of 9, 18, 27, and 36 Å for ligand conjugation and found that glycopeptides with galactosides ligands three helical turns (27 Å) apart best fit LecA. In addition, we tested different galactose derivatives on the selected scaffold (27 Å) to improve the binding avidity to LecA. The results validate a new multivalent scaffold design and provide useful information for LecA inhibitor development.