In vivo supramolecular templating enhances the activity of multivalent ligands: A potential therapeutic against the Escherichia coli O157 AB ₅ toxins

Abstract

We demonstrate that interactions between multimeric receptors and multivalent ligands are dramatically enhanced by recruiting a complementary templating receptor such as an endogenous multimeric protein but only when individual ligands are attached to a polymer as preorganized, covalent, heterobifunctional pairs. This effect cannot be replicated by a multivalent ligand if the same recognition elements are independently arrayed on the scaffold. Application of this principle offers an approach to create highavidity inhibitors for multimeric receptors. Judicious selection of the ligand that engages the templating protein allows appropriate effector function to be incorporated in the polymeric construct, thereby providing an opportunity for therapeutic applications. The power of this approach is exemplified by the design of exceptionally potent Escherichia coli Shiga toxin antagonists that protect transgenic mice that constitutively express a human pentraxin, serum amyloid P component.heterobifunctional ligand ͉ multivalency ͉ Shiga toxin

Structure-dependent Pseudoreceptor Intracellular Traffic of Adamantyl Globotriaosyl Ceramide Mimics

“…The binding affinity of the VT B subunit pentamer for the lipid-free oligosaccharide is much reduced compared with native Gb 3 glycolipid (43), but this can be largely countered by multivalency (41), particularly when tailored to accommodate the pentameric geometry of the receptor B subunits displayed within the VT holotoxin (40,42).…”

Recent Progress of Shiga Toxin Neutralizer for Treatment of Infections by Shiga Toxin-Producing Escherichia coli

“…In this strategy, a polymeric heterobifunctional molecule, named (S)-Poly-BAIT, which recognizes both Stx1 and human serum amyloid P component (HuSAP) through interactions with its trisaccharide moiety and a cyclic pyruvate ketal moiety, respectively, was developed (Kitov et al 2008). HuSAP, which is a circulating plasma protein and a member of the highly conserved pentraxin family, was used as a template protein.…”

Biopolymer, Dendrimer, and Liposome Nanoplatforms for Optical Molecular Imaging

“…However, the in vivo utility of small molecules as therapeutic or imaging agents often faces issues concerning their effective dose, stability, and rapid clearance. The appeal of macromolecular nanoconstructs as carriers is their multivalent and multifunctional attributes that allow high payload of drug molecules and active targeting groups to be incorporated to enhance therapeutic or imaging efficacy [4][5][6]. In addition, the ability to engineer the carrier surface with benign pharmacokinetic and/or biodistribution modifiers may provide a "stealth" environment to prevent uptake by macrophages and prolong in vivo blood half-life [7][8][9].…”