A rapid synthesis of low-nanomolar divalent LecA inhibitors in four linear steps from d-galactose pentaacetate

Abstract

<p>Design and four step synthesis of simple, readily accessible low-nanomolar divalent LecA ligands with selectivity over human galectin-1.</p>

The assessment of Pseudomonas aeruginosa lectin LecA binding characteristics of divalent galactosides using multiple techniques

“…Recently, a related divalent ligand was reported with a similar K d of ca. 11 nM ( Zahorska et al. 2020 ).…”

“…A possible cause of these different numbers in this very relevant comparison is the fact that our spacers contain significantly hydrated glucose units which help solubility but may slow mobility and increase the residence time, in comparison to the more aromatic and hydrophobic spacer of the mentioned 11 nM compound. Unfortunately no direct measurement of the residence time of the monovalent ligands was possible, because of the weak binding and fast kinetics ( Zahorska et al. 2020 ); ( Jayaraman 2009 ).…”

Targeting extracellular lectins of Pseudomonas aeruginosa with glycomimetic liposomes

“…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

“…In case of LecB, we have developed small molecule glycomimetics starting from a mannoside [13–15] via simple C‐glycosides [16] into orally available anti‐biofilm lead compounds [17,18] which are currently under further investigation. 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] …”