HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 43, 32755-32764, October 27, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/43/32755    most recent M603614200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, W. Articles by Lehrer, R. I. Search for Related Content PubMed PubMed Citation Articles by Wang, W. Articles by Lehrer, R. I. Social Bookmarking                      What's this?

Retrocyclins Kill Bacilli and Germinating Spores of Bacillus anthracis and Inactivate Anthrax Lethal Toxin^*

Wei Wang, Chandrika Mulakala¹, Sabrina C. Ward^¶, Grace Jung, Hai Luong, Duy Pham, Alan J. Waring, Yiannis Kaznessis¹, Wuyuan Lu^||, Kenneth A. Bradley, and Robert I. Lehrer²

From the Departments of Medicine and ^¶Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, the Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, Minnesota 55455, and the ^||Institute for Human Virology, Biotechnology Institute, University of Maryland, Baltimore, Maryland 21201

-defensins are cyclic octadecapeptides encoded by the modified -defensin genes of certain nonhuman primates. The recent demonstration that human -defensins could prevent deleterious effects of anthrax lethal toxin in vitro and in vivo led us to examine the effects of -defensins on Bacillus anthracis (Sterne). We tested rhesus -defensins 1-3, retrocyclins 1-3, and several analogues of RC-1. Low concentrations of -defensins not only killed vegetative cells of B. anthracis (Sterne) and rendered their germinating spores nonviable, they also inactivated the enzymatic activity of anthrax lethal factor and protected murine RAW-264.7 cells from lethal toxin, a mixture of lethal factor and protective antigen. Structure-function studies indicated that the cyclic backbone, intramolecular tri-disulfide ladder, and arginine residues of -defensins contributed substantially to these protective effects. Surface plasmon resonance studies showed that retrocyclins bound the lethal factor rapidly and with high affinity. Retrocyclin-mediated inhibition of the enzymatic activity of lethal factor increased substantially if the enzyme and peptide were preincubated before substrate was added. The temporal discrepancy between the rapidity of binding and the slowly progressive extent of lethal factor inhibition suggest that post-binding events, perhaps in situ oligomerization, contribute to the antitoxic properties of retrocyclins. Overall, these findings suggest that -defensins provide molecular templates that could be used to create novel agents effective against B. anthracis and its toxins.

Received for publication, April 14, 2006 , and in revised form, May 30, 2006.

^* The work was also supported in part by National Institutes of Health (NIH) Grants AI056921 (to R. I. L.), AI057870 (to K. B.), and AI061482 (to W. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by NIH Grant GM070989 and by the National Computational Science Alliance (under Grant TG-MCA04T033).

² To whom correspondence should be addressed: Dept. of Medicine, David Geffen School of Medicine, UCLA, 10833 LeConte Ave., Los Angeles, CA 90095. Tel.: 310-825-0133; Fax: 310-206-8766; E-mail: rlehrer{at}mednet.ucla.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. E. Boyer, C. P. Quinn, A. R. Hoffmaster, T. R. Kozel, E. Saile, C. K. Marston, A. Percival, B. D. Plikaytis, A. R. Woolfitt, M. Gallegos, et al. Kinetics of Lethal Factor and Poly-D-Glutamic Acid Antigenemia during Inhalation Anthrax in Rhesus Macaques Infect. Immun., August 1, 2009; 77(8): 3432 - 3441. [Abstract] [Full Text] [PDF]

				R. I. Lehrer, G. Jung, P. Ruchala, S. Andre, H. J. Gabius, and W. Lu Multivalent Binding of Carbohydrates by the Human {alpha}-Defensin, HD5 J. Immunol., July 1, 2009; 183(1): 480 - 490. [Abstract] [Full Text] [PDF]

				A. E. Garcia, G. Osapay, P. A. Tran, J. Yuan, and M. E. Selsted Isolation, Synthesis, and Antimicrobial Activities of Naturally Occurring {theta}-Defensin Isoforms from Baboon Leukocytes Infect. Immun., December 1, 2008; 76(12): 5883 - 5891. [Abstract] [Full Text] [PDF]

				D. E. Dietrich, X. Xiao, D. V. Dawson, M. Belanger, H. Xie, A. Progulske-Fox, and K. A. Brogden Human {alpha}- and {beta}-Defensins Bind to Immobilized Adhesins from Porphyromonas gingivalis Infect. Immun., December 1, 2008; 76(12): 5714 - 5720. [Abstract] [Full Text] [PDF]

				M. W. Lisanby, M. K. Swiecki, B. L. P. Dizon, K. J. Pflughoeft, T. M. Koehler, and J. F. Kearney Cathelicidin Administration Protects Mice from Bacillus anthracis Spore Challenge J. Immunol., October 1, 2008; 181(7): 4989 - 5000. [Abstract] [Full Text] [PDF]

				A. Scorpio, S. A. Tobery, W. J. Ribot, and A. M. Friedlander Treatment of Experimental Anthrax with Recombinant Capsule Depolymerase Antimicrob. Agents Chemother., March 1, 2008; 52(3): 1014 - 1020. [Abstract] [Full Text] [PDF]