{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:21:40Z","timestamp":1760242900587,"version":"build-2065373602"},"reference-count":81,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2016,11,15]],"date-time":"2016-11-15T00:00:00Z","timestamp":1479168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>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\u2013mM 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 \u201cimperfect\u201d PAMAM dendrimers, the mixed-surface G2 75% OH 25% NH2 dendrimer and G3-NH2 dendron. At low voltages, both \u201cimperfect\u201d dendrimers show similar rate constants but significantly weaker voltage sensitivity when compared with the intact G2-NH2 PAMAM dendrimer.<\/jats:p>","DOI":"10.3390\/toxins8110337","type":"journal-article","created":{"date-parts":[[2016,11,15]],"date-time":"2016-11-15T10:25:31Z","timestamp":1479205531000},"page":"337","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Impact of Dendrimer Terminal Group Chemistry on Blockage of the Anthrax Toxin Channel: A Single Molecule Study"],"prefix":"10.3390","volume":"8","author":[{"given":"Goli","family":"Yamini","sequence":"first","affiliation":[{"name":"Department of Biology, The Catholic University of America, Washington DC, WA 20064, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nnanya","family":"Kalu","sequence":"additional","affiliation":[{"name":"Department of Biology, The Catholic University of America, Washington DC, WA 20064, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ekaterina","family":"Nestorovich","sequence":"additional","affiliation":[{"name":"Department of Biology, The Catholic University of America, Washington DC, WA 20064, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2016,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Yamini, G., and Nestorovich, E.M. 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