Numerous carbohydrate binding proteins play decisive roles in the pathogenicity of microorganisms, including bacteria, fungi and viruses. With the uncovering of many of the specificities of these proteins, the possibilities for intervention increases dramatically. This alternative antipathogenic intervention is further driven by the increasing resistance of pathogens against antibiotic and antiviral agents aimed at killing the pathogens. In many cases the carbohydrate binding proteins attaches to cell surface carbohydrates, in a multivalent fashion, to induce colonization and invasion. Multivalent inhibitors are becoming increasingly effective as the rules of multivalency are increasingly being understood. We here will discuss the design and thermodynamic binding, and infection inhibition of aspects of multivalent ligands of the virulence factor lectin LecA of the problematic ESKAPE pathogen P. aeruginosa . Major multivalency effects were observed of approaching 3 orders of magnitude, and varying contributions of enthalpy and entropy. Furthermore, calculations were performed that predict the multivalency effect and correlated well with experiment. The hemagglutinin protein (HA) of the influenza A virus is our other medicinally important target. For this trivalent protein target with widely separated binding sites, large sialyl-LacNac based ligands were synthesized and linked to scaffold molecules. Enhanced inhibition of ca. 400 fold was observed, indicating that chelation between binding sites was achieved. Results will be put in perspective to prior efforts.
- G. Yu, A.C. Vicini, R.J. Pieters, 'Assembling of divalent ligands and their Effect on Divalent Binding to Pseudomonas aeruginosa Lectin LecA', J. Org. Chem. 2019, acs.joc.8b02727.