Obstructing Toxin Pathways by Targeted Pore Blockage

Nestorovich, Ekaterina M.; Bezrukov, Sergey M.

doi:10.1021/cr300141q

Cited by 38 publications

(44 citation statements)

References 599 publications

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“…Excellent reviews have addressed pore blocker molecules and their ability to inhibit PFTs [119,128]. Two families, small cationic blockers and cationic cyclodextrin derivatives, have been mainly investigated.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…Two families, small cationic blockers and cationic cyclodextrin derivatives, have been mainly investigated. The small cationic blockers including tetraalkylammonium, chloroquine, quinacrine and related compounds (see [119]) as mentioned above efficiently inhibit PA and C2-II but poorly Ib. Similarly, positively charged heterocyclic azazolopyridinium salts are efficient inhibitors of anthrax toxins and C2 toxin in cell model [129,130].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…Similarly, positively charged heterocyclic azazolopyridinium salts are efficient inhibitors of anthrax toxins and C2 toxin in cell model [129,130]. The rationale to use cyclodextrin derivatives is to develop low molecular cyclic compound having a shape able to block the toxin pores and to prevent the translocation of the enzymatic components [119]. Cationic beta-cyclodextrin derivatives block ion current through C2-II and Ib pores in lipid bilayer and prevent epithelial cell intoxication by C2, Iota, and CDT toxins [131,132].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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Pore-forming activity of clostridial binary toxins

Knapp

Benz

Popoff

2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Clostridial binary toxins (Clostridium perfringens Iota toxin, Clostridium difficile transferase, Clostridium spiroforme toxin, Clostridium botulinum C2 toxin) as Bacillus binary toxins, including Bacillus anthracis toxins consist of two independent proteins, one being the binding component which mediates the internalization into cell of the intracellularly active component. Clostridial binary toxins induce actin cytoskeleton disorganization through mono-ADP-ribosylation of globular actin and are responsible for enteric diseases. Clostridial and Bacillus binary toxins share structurally and functionally related binding components which recognize specific cell receptors, oligomerize, form pores in endocytic vesicle membrane, and mediate the transport of the enzymatic component into the cytosol. Binding components retain the global structure of pore-forming toxins (PFTs) from the cholesterol-dependent cytotoxin family such as perfringolysin. However, their pore-forming activity notably that of clostridial binding components is more related to that of heptameric PFT family including aerolysin and C. perfringens epsilon toxin. This review focuses upon pore-forming activity of clostridial binary toxins compared to other related PFTs. This article is part of a Special Issue entitled: Pore-Forming Toxins edited by Mauro Dalla Serra and Franco Gambale.

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Section: Accepted Manuscriptmentioning

confidence: 99%

Section: Accepted Manuscriptmentioning

confidence: 99%

Section: Accepted Manuscriptmentioning

confidence: 99%

See 1 more Smart Citation

Pore-forming activity of clostridial binary toxins

Knapp

Benz

Popoff

2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…The binding of the toxic enzyme, LF, to the receptor-bound (PA 63 ) 7 results in the formation of a complex which is internalized by the host cell ( Figure S1). This complex formation is one of the key steps in the intoxication pathway ( Figure S1B), [10,11] and therapeutics have been designed to inhibit these interactions. [3] In previous work, phage display was used to identify a 12-mer peptide (HTSTYWWLDGAP) that binds to (PA 63 ) 7.…”

mentioning

confidence: 99%

“…[14] Structure-based design is a particularly effective strategy to design polyvalent inhibitors of anthrax lethal toxin and other targets. [11][12][13][14][15][16] Ligand spacing and valency are key parameters that influence the efficacy of polyvalent molecules (Scheme 1A). [12][13][14]17] The ligand spacing is simply the distance separating adjacent ligands on a polyvalent molecule.…”

mentioning

confidence: 99%

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

Patke¹,

Boggara²,

Maheshwari³

et al. 2014

Angewandte Chemie

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The design of polyvalent molecules, presenting multiple copies of a specific ligand, represents a promising strategy to inhibit pathogens and toxins. The ability to control independently the valency and the spacing between ligands would be valuable for elucidating structure–activity relationships and for designing potent polyvalent molecules. To that end, we designed monodisperse polypeptide‐based polyvalent inhibitors of anthrax toxin in which multiple copies of an inhibitory toxin‐binding peptide were separated by flexible peptide linkers. By tuning the valency and linker length, we designed polyvalent inhibitors that were over four orders of magnitude more potent than the corresponding monovalent ligands. This strategy for the rational design of monodisperse polyvalent molecules may not only be broadly applicable for the inhibition of toxins and pathogens, but also for controlling the nanoscale organization of cellular receptors to regulate signaling and the fate of stem cells.

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

Patke¹,

Boggara²,

Maheshwari³

et al. 2014

Angew Chem Int Ed

View full text Add to dashboard Cite

The design of polyvalent molecules, presenting multiple copies of a specific ligand, represents a promising strategy to inhibit pathogens and toxins. The ability to control independently the valency and the spacing between ligands would be valuable for elucidating structure-activity relationships and for designing potent polyvalent molecules. To that end, we designed monodisperse polypeptide-based polyvalent inhibitors of anthrax toxin in which multiple copies of an inhibitory toxin-binding peptide were separated by flexible peptide linkers. By tuning the valency and linker length, we designed polyvalent inhibitors that were over four orders of magnitude more potent than the corresponding monovalent ligands. This strategy for the rational design of monodisperse polyvalent molecules may not only be broadly applicable for the inhibition of toxins and pathogens, but also for controlling the nanoscale organization of cellular receptors to regulate signaling and stem cell fate.

show abstract

Obstructing Toxin Pathways by Targeted Pore Blockage

Cited by 38 publications

References 599 publications

Pore-forming activity of clostridial binary toxins

Pore-forming activity of clostridial binary toxins

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

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

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