Next Article in Journal
N-methyl-2-pyridone-5-carboxamide (2PY)—Major Metabolite of Nicotinamide: An Update on an Old Uremic Toxin
Next Article in Special Issue
Clostridium perfringens Sialidases: Potential Contributors to Intestinal Pathogenesis and Therapeutic Targets
Previous Article in Journal
Comparison of In-Solution Biorecognition Properties of Aptamers against Ochratoxin A
Previous Article in Special Issue
Chloroquine Analog Interaction with C2- and Iota-Toxin in Vitro and in Living Cells
Article Menu
Issue 11 (November) cover image

Export Article

Open AccessArticle
Toxins 2016, 8(11), 337; doi:10.3390/toxins8110337

Impact of Dendrimer Terminal Group Chemistry on Blockage of the Anthrax Toxin Channel: A Single Molecule Study

Department of Biology, The Catholic University of America, Washington DC, WA 20064, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Holger Barth
Received: 18 October 2016 / Revised: 7 November 2016 / Accepted: 7 November 2016 / Published: 15 November 2016
(This article belongs to the Special Issue Novel Pharmacological Inhibitors for Bacterial Protein Toxins)
View Full-Text   |   Download PDF [3167 KB, uploaded 15 November 2016]   |  

Abstract

Nearly all the cationic molecules tested so far have been shown to reversibly block K+ current through the cation-selective PA63 channels of anthrax toxin in a wide nM–mM range of effective concentrations. A significant increase in channel-blocking activity of the cationic compounds was achieved when multiple copies of positively charged ligands were covalently linked to multivalent scaffolds, such as cyclodextrins and dendrimers. Even though multivalent binding can be strong when the individual bonds are relatively weak, for drug discovery purposes we often strive to design multivalent compounds with high individual functional group affinity toward the respective binding site on a multivalent target. Keeping this requirement in mind, here we perform a single-channel/single-molecule study to investigate kinetic parameters of anthrax toxin PA63 channel blockage by second-generation (G2) poly(amido amine) (PAMAM) dendrimers functionalized with different surface ligands, including G2-NH2, G2-OH, G2-succinamate, and G2-COONa. We found that the previously reported difference in IC50 values of the G2-OH/PA63 and G2-NH2/PA63 binding was determined by both on- and off-rates of the reversible dendrimer/channel binding reaction. In 1 M KCl, we observed a decrease of about three folds in k o n and a decrease of only about ten times in t r e s with G2-OH compared to G2-NH2. At the same time for both blockers, k o n and t r e s increased dramatically with transmembrane voltage increase. PAMAM dendrimers functionalized with negatively charged succinamate, but not carboxyl surface groups, still had some residual activity in inhibiting the anthrax toxin channels. At 100 mV, the on-rate of the G2-succinamate binding was comparable with that of G2-OH but showed weaker voltage dependence when compared to G2-OH and G2-NH2. The residence time of G2-succinamate in the channel exhibited opposite voltage dependence compared to G2-OH and G2-NH2, increasing with the cis-negative voltage increase. We also describe kinetics of the PA63 ion current modulation by two different types of the “imperfect” PAMAM dendrimers, the mixed-surface G2 75% OH 25% NH2 dendrimer and G3-NH2 dendron. At low voltages, both “imperfect” dendrimers show similar rate constants but significantly weaker voltage sensitivity when compared with the intact G2-NH2 PAMAM dendrimer. View Full-Text
Keywords: multivalency; planar lipid bilayer technique; Bacillus anthracis; protective antigen; pore blockage multivalency; planar lipid bilayer technique; Bacillus anthracis; protective antigen; pore blockage
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Supplementary material

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

Yamini, G.; Kalu, N.; Nestorovich, E.M. Impact of Dendrimer Terminal Group Chemistry on Blockage of the Anthrax Toxin Channel: A Single Molecule Study. Toxins 2016, 8, 337.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Toxins EISSN 2072-6651 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top