Stable peptide inhibitors prevent binding of lethal and oedema factors to protective antigen and neutralize anthrax toxin in vivo.
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.
Pini
Alessandro
A
Department of Molecular Biology, University of Siena, Via Fiorentina 1, 53100 Siena, Italy.
Runci
Ylenia
Y
Falciani
Chiara
C
Lelli
Barbara
B
Brunetti
Jlenia
J
Pileri
Silvia
S
Fabbrini
Monica
M
Lozzi
Luisa
L
Ricci
Claudia
C
Bernini
Andrea
A
Tonello
Fiorella
F
Dal Molin
Federica
F
Neri
Paolo
P
Niccolai
Neri
N
Bracci
Luisa
L
D000595:Amino Acid Sequence; D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism*; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000096:biosynthesis; D019151:Peptide Library; D010455:Peptides / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D014757:Viper Venoms / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D009842:Oligopeptides; D019151:Peptide Library; D010455:Peptides; D014757:Viper Venoms; C030325:anthrax toxin; C416405:edema factor; D000242:Cyclic AMP