Inhibitors of pore-forming toxins

Bezrukov, Sergey M.; Nestorovich, Ekaterina M.

doi:10.1016/b978-0-12-800188-2.00038-0

Cited by 2 publications

(1 citation statement)

References 202 publications

(295 reference statements)

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“…A common mechanism of bacterial virulence is the secretion of exotoxins, many of which form ion channels in the mammalian cell membranes (1)(2)(3). The water-filled ion channels represent a feasible and well-defined target to be investigated in rational antitoxin design studies (3)(4)(5), including those performed on a single-molecule level using the high-resolution lipid bilayer membrane assay. These approaches explore the unique individual properties of target biomolecules as well as small and macromolecule drug candidates, aiming to reveal and manipulate the physical forces involved in their interaction.…”

Section: Introductionmentioning

confidence: 99%

Exploring the Nature of Cationic Blocker Recognition by the Anthrax Toxin Channel

Abolfath

Kolberg

Karginov

et al. 2019

Biophysical Journal

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Obstructing conductive pathways of the channel-forming toxins with targeted blockers is a promising drug design approach. Nearly all tested positively charged ligands have been shown to reversibly block the cation-selective channel-forming protective antigen (PA 63) component of the binary anthrax toxin. The cationic ligands with more hydrophobic surfaces, particularly those carrying aromatic moieties, inhibited PA 63 more effectively. To understand the physical basis of PA 63 selectivity for a particular ligand, detailed information is required on how the blocker structural elements (e.g., positively charged and aromatic groups) influence the molecular kinetics of the blocker/channel binding reactions. In this study, we address this problem using the highresolution single-channel planar lipid bilayer technique. Several structurally distinct cationic blockers, namely per-6-S-(3-amino) propyl-b-cyclodextrin, per-6-S-(3-aminomethyl) benzyl-a-cyclodextrin, per-6-S-(3-aminomethyl) benzyl-b-cyclodextrin, per-6-S-(3-aminomethyl) benzyl-g-cyclodextrin, methyltriphenylphosphonium ion, and G0 polyamidoamine dendrimer are tested for their ability to inhibit the heptameric and octameric PA 63 variants and PA 63 F427A mutant. The F427 residues form a hydrophobic constriction region inside the channel, known as the ''f-clamp.'' We show that the cationic blockers interact with PA 63 through a combination of forces. Analysis of the binding reaction kinetics suggests the involvement of cation-p, Coulomb, and salt-concentration-independent p-p or hydrophobic interactions in the cationic cyclodextrin binding. It is possible that these blockers bind to the f-clamp and are also stabilized by the Coulomb interactions of their terminal amino groups with the water-exposed negatively charged channel residues. In PA 63 F427A, only the suggested Coulomb component of the cyclodextrin interaction remains. Methyltriphenylphosphonium ion and G0 polyamidoamine dendrimer, despite being positively charged, interact primarily with the f-clamp. We also show that seven-and eightfold symmetric cyclodextrins effectively block the heptameric and octameric forms of PA 63 interchangeably, adding flexibility to the earlier formulated blocker/target symmetry match requirement.

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Section: Introductionmentioning

confidence: 99%

Exploring the Nature of Cationic Blocker Recognition by the Anthrax Toxin Channel

Abolfath

Kolberg

Karginov

et al. 2019

Biophysical Journal

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Inhibiting bacterial toxins by channel blockage

Bezrukov

Nestorovich

2015

Pathogens and Disease

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Emergent rational drug design techniques explore individual properties of target biomolecules, small and macromolecule drug candidates, and the physical forces governing their interactions. In this minireview, we focus on the single-molecule biophysical studies of channel-forming bacterial toxins that suggest new approaches for their inhibition. We discuss several examples of blockage of bacterial pore-forming and AB-type toxins by the tailor-made compounds. In the concluding remarks, the most effective rationally designed pore-blocking antitoxins are compared with the small-molecule inhibitors of ion-selective channels of neurophysiology.

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Inhibitors of pore-forming toxins

Cited by 2 publications

References 202 publications

Exploring the Nature of Cationic Blocker Recognition by the Anthrax Toxin Channel

Exploring the Nature of Cationic Blocker Recognition by the Anthrax Toxin Channel

Inhibiting bacterial toxins by channel blockage

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