Nanomolar cholera toxininhibitors based on symmetrical pentavalent ganglioside GM1os-sym-corannulenes

Abstract

Eight symmetric and pentavalent corannulene derivatives were functionalized with galactose and the ganglioside GM1-oligosaccharide (GM1os) via copper-catalyzed alkyne-azide cycloaddition (CuAAC) reactions. The compounds were evaluated for their ability to inhibit the binding of the pentavalent cholera toxin to its natural ligand, ganglioside GM1. In this assay, all ganglioside GM1os-sym-corannulenes proved to be highly potent nanomolar inhibitors of cholera toxin.

Towards new cholera prophylactics and treatment: Crystal structures of bacterial enterotoxins in complex with GM1 mimics

“…Lately the search has turned towards multivalent inhibitors 36 , e.g . using pentavalent GM1-os on different scaffolds, creating a 1:1 interaction of toxin and inhibitor 37, 38 . An interesting approach is to “let CT fight itself” using CTB modified with GM1-os residues as penta-GM1-os-CTB neoglycoprotein inhibitors 39 .…”

Supramolecular glycopolymers with thermo-responsive self-assembly and lectin binding

“…Thermo-responsive polymers, such as poly(N-isopropyl acrylamide) (PNIPAM), undergo a reversible phase transition from hydrophilic to hydrophobic when their solution temperature is raised above their LCST, changing from an extended chain conformation below LCST into a collapsed chain above LCST. 6,[32][33][34][35][36][37] In general, the interaction of a lectin with a carbohydrate is quite weak, but can be dramatically enhanced by the multivalent effect of glycopolymers, which is known as the "glycocluster Scheme 1 Synthesis of the triblock copolymer by sequential RAFT polymerization and its host-guest interaction with self-assembly behaviour. In general, the LCST of PNIPAM can be influenced by several factors, e.g.…”

A Protein‐Based Pentavalent Inhibitor of the Cholera Toxin B‐Subunit

“…[5] Their modular approach showed that matching precisely the size and spacing of the ligands to the binding sites of CTB could optimize the inhibitory potential. [5b, 6] Other recent studies have used GM1os ligands on both corannulene [7] and calixarene cores. [8] These pentavalent structures gave IC 50 values down to 5 nm and 450 pm, respectively.…”

“…[7,8] The ability of CTB to bind to a GM1-coated microtiter plate was assessed across a wide range of inhibitor concentrations. Pentavalent ligand W88E(GM1) exhibited an exceptionally low IC 50 value of 104 pm ( Figure 2 and Table 1), making it the most potent pentavalent ligand reported thus far.…”