{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T13:15:16Z","timestamp":1723468516012},"reference-count":45,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2007,1,1]],"date-time":"2007-01-01T00:00:00Z","timestamp":1167609600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2007,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            In the course of\n            <jats:italic>Bacillus anthracis<\/jats:italic>\n            infection,\n            <jats:italic>B. anthracis<\/jats:italic>\n            lethal factor (LF) and edema factor bind to a protective antigen (PA) associated with cellular receptors ANTXR1 (TEM8) or ANTXR2 (CMG2), followed by internalization of the complex via receptor-mediated endocytosis. A new group of potential antianthrax drugs, \u03b2-cyclodextrins, has recently been described. A member of this group, per-6-(3-aminopropylthio)-\u03b2-cyclodextrin (AmPr\u03b2CD), was shown to inhibit the toxicity of LF in vitro and in vivo. In order to determine which steps in lethal factor trafficking are inhibited by AmPr\u03b2CD, we developed two targeted fluorescent tracers based on LFn, a catalytically inactive fragment of LF: (i) LFn site specifically labeled with the fluorescent dye AlexaFluor-594 (LFn-Al), and (ii) LFn-decorated liposomes loaded with the fluorescent dye 8-hydroxypyrene-1,3,6-trisulfonic acid (LFn-Lip). Both tracers retained high affinity to PA\/ANTXR complexes and were readily internalized via receptor-mediated endocytosis. Using fluorescent microscopy, we found that AmPr\u03b2CD inhibits receptor-mediated cell uptake but not the binding of LFn-Al to PA\/ANTXR complexes, suggesting that AmPr\u03b2CD works outside the cell. Moreover, AmPr\u03b2CD and LFn-Al synergistically protect RAW 264.7 cells from PA-mediated LF toxicity, confirming that AmPr\u03b2CD did not affect the binding of LFn-Al to receptor-associated PA. In contrast, AmPr\u03b2CD did not inhibit PA-mediated internalization of LFn-Lip, suggesting that multiplexing of LFn on the liposomal surface overcomes the inhibiting effects of AmPr\u03b2CD. Notably, internalized LFn-Al and LFn-Lip protected cells that overexpressed anthrax receptor TEM8 from PA-induced, LF-independent toxicity, suggesting an independent mechanism for PA inhibition inside the cell. These data suggest the potential for the use of \u03b2-cyclodextrins in combination with LFn-Lip loaded with antianthrax drugs against intracellular targets.\n          <\/jats:p>","DOI":"10.1128\/aac.00983-06","type":"journal-article","created":{"date-parts":[[2006,12,20]],"date-time":"2006-12-20T18:32:51Z","timestamp":1166639571000},"page":"245-251","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":20,"title":["Inhibition of Anthrax Protective Antigen Outside and Inside the Cell"],"prefix":"10.1128","volume":"51","author":[{"given":"Marina V.","family":"Backer","sequence":"first","affiliation":[{"name":"SibTech, Inc., Newington, Connecticut 06111"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vimal","family":"Patel","sequence":"additional","affiliation":[{"name":"SibTech, Inc., Newington, Connecticut 06111"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian T.","family":"Jehning","sequence":"additional","affiliation":[{"name":"SibTech, Inc., Newington, Connecticut 06111"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin P.","family":"Claffey","sequence":"additional","affiliation":[{"name":"University of Connecticut, Health Center, Farmington, Connecticut 06030"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladimir A.","family":"Karginov","sequence":"additional","affiliation":[{"name":"Innovative Biologics, Inc., Manassas, Virginia 20110"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph M.","family":"Backer","sequence":"additional","affiliation":[{"name":"SibTech, Inc., Newington, Connecticut 06111"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200211018"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)53698-X"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1021\/bc015534j"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1021\/bc060037u"},{"key":"e_1_3_2_6_2","first-page":"35","volume":"289","year":"2004","unstructured":"Backer, M. 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