title: Efficacy and toxicity of the antimicrobial peptide M33 produced with different counter-ions.
abstract: The tetra-branched peptide M33 (Pini et al. in FASEB J 24:1015-1022, 2010) is under evaluation in animal models for its activity as antimicrobial agent in lung infections and sepsis. The preclinical development of a new drug requires medium-scale manufacture for tests of efficacy, biodistribution, pharmacokinetics and toxicity. In order to produce the most suitable peptide form for these purposes, we evaluated the behaviour of the peptide M33 obtained with different counter-ions. We compared activity and toxicity in vitro and in vivo of the peptide M33 produced as trifluoroacetate salt (TFacetate) and as acetate salt. The two forms did not differ substantially in terms of efficacy in vitro or in vivo but showed different toxicities for human cells and in animals. M33-TFacetate proved to be 5-30% more toxic than M33-acetate for cells derived from normal bronchi and cells carrying ΔF508 mutation in the CFTR gene, the most frequent variant in cystic fibrosis. M33-TFacetate produced manifest signs of in vivo toxicity immediately after administration, whereas M33-acetate only generated mild signs, which disappeared within a few hours. The peptide M33-acetate proved more suitable for the development of a new drug, and was therefore chosen for further characterization.
authors: Dipartimento di Biotecnologie, Università degli Studi di Siena, and Azienda Ospedaliera Universitaria Senese, Policlinico Le Scotte, Via Fiorentina 1, Siena, Italy. pinia@unisi.it
authors: Alessandro
authors: A
authors: Pini
authors: Luisa
authors: L
authors: Lozzi
authors: Andrea
authors: A
authors: Bernini
authors: Jlenia
authors: J
authors: Brunetti
authors: Chiara
authors: C
authors: Falciani
authors: Silvia
authors: S
authors: Scali
authors: Stefano
authors: S
authors: Bindi
authors: Tiziana
authors: T
authors: Di Maggio
authors: Gian Maria
authors: GM
authors: Rossolini
authors: Neri
authors: N
authors: Niccolai
authors: Luisa
authors: L
authors: Bracci
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity*; D001980:Bronchi / Q000166:cytology; D002460:Cell Line; D016971:Citrobacter freundii / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects*; D004926:Escherichia coli / Q000187:drug effects; D004927:Escherichia coli Infections / Q000188:drug therapy*; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D010446:Peptide Fragments / Q000494:pharmacology; D011549:Pseudomonas / Q000187:drug effects; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects*
chemical_list: D023181:Antimicrobial Cationic Peptides; D010446:Peptide Fragments