Multivalent Inhibitors of Channel-Forming Bacterial Toxins

Abstract

Rational design of multivalent molecules represents a remarkable modern tool to transform weak non-covalent interactions into strong binding by creating multiple finely-tuned points of contact between multivalent ligands and their supposed multivalent targets. Here, we describe several prominent examples where the multivalent blockers were investigated for their ability to directly obstruct oligomeric channel-forming bacterial exotoxins, such as the pore-forming bacterial toxins and B component of the binary bacterial toxins. We address problems related to the blocker/target symmetry match and nature of the functional groups, as well as chemistry and length of the linkers connecting the functional groups to their multivalent scaffolds. Using the anthrax toxin and AB5 toxin case studies, we briefly review how the oligomeric toxin components can be successfully disabled by the multivalent non-channel-blocking inhibitors, which are based on a variety of multivalent scaffolds.

Fig. 1

Multivalent channel-blocking inhibitors of PA₆₃ of anthrax toxin. a Illustration of the idea: a multivalent blocker as effective inhibitor of PA₆₃ of tripartite anthrax toxin. b The most prominent examples of the multivalent blockers are based on cyclodextrin (Karginov et al. 2005) (top) and dendrimer (Forstner et al. 2014) (bottom) scaffolds

Fig. 2

Multivalent non-channel-blocking inhibitors of PA₆₃ of anthrax toxin. a Peptide-based inhibitors. b Cyclodextrin-based inhibitor of anthrax toxin complexes assembly. c Liposome-based inhibitor of anthrax toxin complexes assembly. Reprinted with permission from Joshi et al. (2011), Rai et al. (2006), and Gujraty et al. (2005). © 2005, 2011. American Chemical Society. © 2006. Nature Publishing Group

Fig. 3

Multivalent inhibitors of AB5 bacterial toxins. a A schematic representation of polymeric preordered heterobifunctional ligands. b Conceptual design of pentavalent inhibitors based on symmetrical core, variable number of linker units, and monovalent fingers blocking the toxin receptor binding site. Reprinted with permission from Kitov et al. (2008) and Merritt et al. (2002). © 2008 National Academy of Sciences, USA. © 2002 American Chemical Society