Novel Chemotypes for Inhibition of Bacterial and Mammalian Carbohydrate-Binding Proteins

Abstract

The carbohydrate-binding proteins (lectins) emerged as viable targets to combat viral as well as bacterial pathogens. Therefore, drugs targeting lectins are desired; however their identification and development is challenging and is currently primarily focused on carbohydrate−based inhibitors. Therefore, new strategies and sensitive methods are required. Fragment-based drug design (FBDD) has proven to be a promising strategy for approaching difficult targets such as lectins. To address the current limitations in design of drug-like inhibitors for lectins, non- and metal-dependent bacterial or mammalian lectins are used. First, bacterial lectins from the opportunistic human pathogens Pseudomonas aeruginosa (LecA (PA-IL) and LecB (PA-IIL)) and Burkholderia ambifaria (BambL) were employed as models to establish ligand- (F- glycan) and protein-observed 19F NMR (PrOF) methods for drug discovery. To demonstrate the utility of these methods for fragment-based drug discovery (FBDD), a druggable pocket in BambL was uncovered as a potential target site for allosteric inhibitors. Finally, these methods were employed as well as other biophysical (X-ray, SPR), computational and biochemical techniques to discover a novel class of drug-like molecules for targeting the carbohydrate-binding site of metal-dependent bacterial and mammalian lectins. Together, the 19F NMR-based methods and discovery of metal- binding pharmacophores (MBPs) as novel chemotypes will support the development of small molecule inhibitors for metal-dependent lectins and bacterial lectins as new therapeutic approaches against antibiotic-resistant pathogens.