Manipulation of Electrostatic and Saccharide Linker Interactions in the Design of Efficient Glycopolypeptide‐Based Cholera Toxin Inhibitors

Abstract

Multivalent, glycopolymer inhibitors designed for the treatment of disease and pathogen infection have shown improvements in binding correlated with general changes in glycopolymer architecture and composition. We have previously demonstrated that control of glycopolypeptide backbone extension and ligand spacing significantly impacts the inhibition of the cholera toxin B subunit pentamer (CT B5) by these polymers. In the studies reported here, we elucidate the role of backbone charge and linker length in modulating the inhibition event. Peptides of the sequence AXPXG (where X is a positive, neutral or negative amino acid), equipped with the alkyne functionality of propargyl glycine, were designed and synthesized via solid-phase peptide synthetic methods and glycosylated via Cu(I)-catalyzed alkyne-azide cycloaddition reactions. The capacity of the glycopeptides to inhibit the binding of the B5 subunit of cholera toxin was evaluated. These studies indicated that glycopeptides with a negatively charged backbone show improved inhibition of the binding event relative to the other glycopeptides. In addition, variations in the length of the linker between the peptide and the saccharide ligand also affected the inhibition of CT by the glycopeptides. Our findings suggest that, apart from appropriate saccharide spacing and polypeptide chain extension, saccharide linker conformation and the systematic placement of charges on the polypeptide backbone are also significant variables that can be tuned to improve the inhibitory potencies of glycopolypeptide-based multivalent inhibitors.

Polysaccharide‐Containing Block Copolymers: Synthesis, Properties and Applications of an Emerging Family of Glycoconjugates

“…The design of glycoprotein-mimics is a current topic of high interest where most of the systems developed so far are graft systems. [10,[133][134][135] Combining recent synthetic developments with chemical routes reviewed herein might allow to synthesize more complex glycopeptide systems with block and graft polysaccharide segments in a same macromolecule. Such a biomimetic approach may open new routes in synthesis and self-assembly communities, allowing a better understanding of the synthetic/biology interface and the development of emerging technologies.…”

Design of Monodisperse and Well‐Defined Polypeptide‐Based Polyvalent Inhibitors of Anthrax Toxin

“…[11][12][13][14][15][16] Ligand spacing and valency are key parameters that influence the efficacy of polyvalent molecules (Scheme 1 A). [12][13][14]17] The ligand spacing is simply the distance separating adjacent ligands on a polyvalent molecule. [5,13,14] Matching the ligand spacing on the polyvalent molecule to the distance between ligand binding sites on the target molecule has been shown to be an effective strategy to design potent polyvalent ligands.…”

Poly(bromoethyl acrylate): A Reactive Precursor for the Synthesis of Functional RAFT Materials

“…14,22,65,66 Nevertheless, these attachments create additional linker groups such as triazoles that may impact on binding affinity. 67,68 The presented substitution of BEA does not create such expansive linkers. Given the success of the thio-bromo substitution using thiophenol, we used the commercially available thiolated sugar, β-thioglucose sodium salt.…”