title: Cationic PAMAM dendrimers as pore-blocking binary toxin inhibitors.
abstract: Dendrimers are unique highly branched macromolecules with numerous groundbreaking biomedical applications under development. Here we identified poly(amido amine) (PAMAM) dendrimers as novel blockers for the pore-forming B components of the binary anthrax toxin (PA63) and Clostridium botulinum C2 toxin (C2IIa). These pores are essential for delivery of the enzymatic A components of the internalized toxins from endosomes into the cytosol of target cells. We demonstrate that at low μM concentrations cationic PAMAM dendrimers block PA63 and C2IIa to inhibit channel-mediated transport of the A components, thereby protecting HeLa and Vero cells from intoxication. By channel reconstitution and high-resolution current recording, we show that the PAMAM dendrimers obstruct transmembrane PA63 and C2IIa pores in planar lipid bilayers at nM concentrations. These findings suggest a new potential role for the PAMAM dendrimers as effective polyvalent channel-blocking inhibitors, which can protect human target cells from intoxication with binary toxins from pathogenic bacteria.
authors: Institute of Pharmacology and Toxicology, University of Ulm Medical Center , D-89081 Ulm, Germany.
authors: Philip
authors: P
authors: Förstner
authors: Fabienne
authors: F
authors: Bayer
authors: Nnanya
authors: N
authors: Kalu
authors: Susanne
authors: S
authors: Felsen
authors: Christina
authors: C
authors: Förtsch
authors: Abrar
authors: A
authors: Aloufi
authors: David Y W
authors: DY
authors: Ng
authors: Tanja
authors: T
authors: Weil
authors: Ekaterina M
authors: EM
authors: Nestorovich
authors: Holger
authors: H
authors: Barth
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D001672:Biocompatible Materials / Q000737:chemistry* / Q000494:pharmacology; D001692:Biological Transport; D001905:Botulinum Toxins / Q000037:antagonists & inhibitors*; D002412:Cations / Q000737:chemistry*; D002522:Chlorocebus aethiops; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D050091:Dendrimers / Q000737:chemistry* / Q000494:pharmacology; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry; D014709:Vero Cells
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D001672:Biocompatible Materials; D002412:Cations; D050091:Dendrimers; D008051:Lipid Bilayers; C104700:PAMAM Starburst; C030325:anthrax toxin; D001905:Botulinum Toxins; C096324:botulinum toxin type C