Non‐Carbohydrate Glycomimetics as Inhibitors of Calcium(II)‐Binding Lectins

Abstract

Because of the antimicrobial resistance crisis,lectins are considered novel drug targets.P seudomonas aeruginosa utilizes LecA and LecB in the infection process.I nhibition of both lectins with carbohydrate-derived molecules can reduce biofilm formation to restore antimicrobial susceptibility.Here, we focused on non-carbohydrate inhibitors for LecA to explore new avenues for lectin inhibition. From as creening cascade we obtained one experimentally confirmed hit, ac atechol, belonging to the well-known PAINS compounds. Rigorous analyses validated electron-deficient catechols as millimolar LecA inhibitors.T he first co-crystal structure of anon-carbohydrate inhibitor in complex with abacterial lectin clearly demonstrates the catechol mimicking the binding of natural glycosides with LecA. Importantly,c atechol 3 is the first non-carbohydrate lectin ligand that binds bacterial and mammalian calcium(II)-binding lectins,g iving rise to this fundamentally new class of glycomimetics.

Targeting extracellular lectins of Pseudomonas aeruginosa with glycomimetic liposomes

“…With the liposomes in hand, we first studied their binding to the lectins LecA or LecB in established competitive binding assays [39][40][41] (Figure 1). The specificity of the LecA-targeted liposomes carrying glycolipid 16 for LecA and the LecB-targeted liposomes carrying glycolipid 17 for LecB was established, untargeted plain liposomes were added at comparable DSPC/Chol concentrations and showed no sign of inhibition.…”

“…We and others have therefore previously used these lectins as targets for antibiofilm agents 2,[33][34][35][36][37] . Our group has developed diverse glycomimetic inhibitors for LecA ranging from various galactosides to catechols [38][39][40] and for LecB originating from modified mannosides 35,41,42 and evolving into C-glycosidic sulfonamides 35,36,43 . Furthermore, we have shown that a LecA-directed fluorescein-conjugate of a covalently binding epoxygalactoheptose moiety can be used to image bacterial biofilms in vitro 44 .…”

Targeting the Central Pocket of the Pseudomonas aeruginosa Lectin LecA

“…Potent monovalent glycomimetics have been proven difficult to obtain for galactophilic LecA, [19–21] thus requiring divalent ligands that display two galactose residues to simultaneously bind to two adjacent binding sites in the LecA tetramer and yield low nanomolar LecA inhibitors [22,23] . In addition, we have recently reported conceptionally new approaches for targeting LecA, i. e. covalent lectin inhibitors [24] and non‐carbohydrate glycomimetics mimicking the binding pattern of carbohydrates [25] …”

“…[22,23] In addition, we have recently reported conceptionally new approaches for targeting LecA, i. e. covalent lectin inhibitors [24] and non-carbohydrate glycomimetics mimicking the binding pattern of carbohydrates. [25] For LecA, inhibitor design generally started from the monosaccharide galactose (Figure 1A) [10] which is the binding epitope from its natural ligand in human, glycosphingolipid Gb3, a host cell surface receptor mediating the engulfment of P. aeruginosa into host cells. [26] Galactose forms an extensive hydrogen bonding network with LecA using all hydroxy groups.…”

Medicinal chemistry of the myeloid C-type lectin receptors Mincle, Langerin, and DC-SIGN

“…Moreover, it was recently demonstrated that catechol-containing fragments can even directly compete with carbohydrate ligands in the primary binding site. 87 …”