Multifunctional multivalency: a focused library of polymeric cholera toxin antagonists

Abstract

Structural pre-organization of the multivalent ligands is important for successful interaction with multimeric proteins. Polymer-based heterobifunctional ligands that contain pendant groups prearranged into heterodimers can be used to probe the active site and surrounding area of the receptor. Here we describe the synthesis and activities of a series of galactose conjugates on polyacrylamide and dextran. Conjugation of a second fragment resulted in nanomolar inhibitors of cholera toxin, while the galactose-only progenitors showed no detectable activity.

Structure Based Design of Cholera Toxin Antagonists

“…Dendrimers bearing two, four and eight GM1 sugars were evaluated by ELISA, the IC 50 values for these compounds were 2 nM, 0.2 nM and 50 pM, respectively. The most recent example of using multivalent strategy in the design of Cholera toxin inibitors presented in this chapter is based on the work of Tran and collaborators (Tran, Kitov et al 2011). They are intensively working on designing a bidentate multivalent ligands.…”

Enhanced Inhibition of Protein Carbohydrate Interactions by Dendritic Multivalent Glycoligands

“…Besides the multivalency approach a structure-based approach of optimizing monovalent ligands has also been ongoing (23). Recently such an improvement strategy was combined with the attachment of the newly built ligands to a multivalent polymeric backbone such as dextran (24). Very potent compounds resulted from the study as exemplified by 15, which surprisingly contained an α-linked galactoside, in contrast to the natural ligand GM1os which contains β-linkages.…”

Polymer antidotes for toxin sequestration

“…Incorporation of these design attributes may further increase the inhibitory power of these dendrimers into the sub-nM regime. To identify ligands with high affinity to CT and LT, Bundle et al have applied a ligand preorganization strategy, and used a linear polyacrylamide backbone to facilitate the synthesis, purification and screening of novel heterobifunctional ligands that bind CT-B and LT-B [66]. Of the saccharides that make up GM1os, the thermodynamic binding of monomeric galactose to CT-B was reported to be K d ≈14 mM while the monomeric neuraminic acid, which binds adjacent to the galactose moiety, has a much weaker interaction (K d ≈210 mM ) [58].…”