The development of small molecular weight glycomimetic drugs has been steadily increasing during the last 20 years. These molecules target various proteins by acting as high-affinity decoys which mimic large cell-surface carbohydrates involved in a variety of key biological processes. Many of these carbohydrate-protein interactions (CPIs) are key molecular recognition events that are implicated in a diverse array of diseases including inflammation, cancer, and infectious diseases. The latest and most intensive research in this area has been focused on the rational design of glycomimetic bacterial lectin antagonists. Examples include mannoside and galactoside ligands targeting the FimH, PapG and FmlH lectins of chaperone usher pathway pili of uropathogenic Escherichia coli, important in the pathogenesis of urinary tract infections (UTIs) and Crohn's Disease. Others include glycoside antagonists of LecA and LecB in Pseudomonas aeruginosa a major causative agent of severe tissue wounds and burns as well as pneumonia, especially in cystic fibrosis patients. We have used X-ray crystallography to design tight-binding ligands of FimH and FmlH which are effective at blocking bacterial binding and clearing UTIs in vivo. A common feature of the most potent analogs is a substituted biphenyl or biaryl aglycone. We discovered that a para-biaryl group is preferred in mannoside FimH antagonists while and ortho-biaryl group is optimal for the galactoside FmlH ligands. We have also elucidated through molecular docking and initial data that a meta-biaryl aglycone is ideal for other lectins. This data, taken with the numerous other reported glycomimetics that often contain a biphenyl, biaryl or one-atom spaced biaryl (e.g. ether) strongly suggest that these aglycone two-ring systems are closely mimicking the electronic and steric properties of a disaccharide. In most cases there is a well-defined one-sugar binding pocket thus rationalizing the requirement for at least one sugar (α-mannose for FimH, β-galactose for FmlH and LecA, α-galactose for PapG and fucose for LecB). The shape of the extended binding surface surrounding the sugar pocket (e.g. tyrosine gate in FimH), which is determined by its carbohydrate receptor binding epitope, can be effectively mimicked with a monosaccharide bearing an appropriately substituted biaryl ring aglycone. This strategy will be useful in expediting the development of future glycomimetic lectin antagonists as novel anti-infective agents.

Glycomimetic lectin antagonists: Are biaryl ring systems universal disaccharide mimics

ACS Spring Meeting 2021

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