Biochem. J. (2006) 395
(157–163) (Printed in Great Britain)
Stable peptide inhibitors prevent binding of lethal and oedema factors to protective antigen and neutralize anthrax toxin in vivo
Alessandro PINI*, Ylenia RUNCI*, Chiara FALCIANI*, Barbara LELLI*, Jlenia BRUNETTI*, Silvia PILERI*, Monica FABBRINI*, Luisa LOZZI*, Claudia RICCI*, Andrea BERNINI*, Fiorella TONELLO†, Federica DAL MOLIN‡, Paolo NERI*, Neri NICCOLAI* and Luisa BRACCI*1
*Department of Molecular Biology, University of Siena, Via Fiorentina 1, 53100 Siena, Italy, †Neuroscience Institute, CNR, 35121 Padova, Italy, and ‡Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy
The lethal and oedema toxins produced by Bacillus anthracis, the aetiological agent of anthrax, are made by association of protective antigen with lethal and oedema factors and play a major role in the pathogenesis of anthrax. In the present paper, we describe the production of peptide-based specific inhibitors in branched form which inhibit the interaction of protective antigen with lethal and oedema factors and neutralize anthrax toxins in vitro and in vivo. Anti-protective antigen peptides were selected from a phage library by competitive panning with lethal factor. Selected 12-mer peptides were synthesized in tetra-branched form and were systematically modified to obtain peptides with higher affinity and inhibitory efficiency.
Key words: anthrax in vivo inhibitor, anthrax toxin, multiple antigen peptide (MAP), oedema factor, peptide stability, phage peptide.
Abbreviations used: EF, oedema factor; Fmoc, fluoren-9-ylmethoxycarbonyl; HBS, Hepes-buffered saline; LF, lethal factor; MALDI–TOF, matrix-assisted laser-desorption ionization–time-of-flight; MAP, multiple antigen peptide; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide; PA, protective antigen.
1To whom correspondence should be addressed (email braccil@unisi.it).
Received 28 October 2005/5 January 2006; accepted 9 January 2006
Published as BJ Immediate Publication 9 January 2006, doi:10.1042/BJ20051747
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