title: Differential In Vitro and In Vivo Toxicities of Antimicrobial Peptide Prodrugs for Potential Use in Cystic Fibrosis.
abstract: There has been considerable interest in the use of antimicrobial peptides (AMPs) as antimicrobial agents for the treatment of many conditions, including cystic fibrosis (CF). The challenging conditions of the CF patient lung require robust AMPs that are active in an environment of high proteolytic activity but that also have low cytotoxicity and immunogenicity. Previously, we developed prodrugs of AMPs that limited the cytotoxic effects of AMP treatment by rendering the antimicrobial activity dependent on the host enzyme neutrophil elastase (NE). However, cytotoxicity remained an issue. Here, we describe the further optimization of the AMP prodrug (pro-AMP) model for CF to produce pro-WMR, a peptide with greatly reduced cytotoxicity (50% inhibitory concentration against CFBE41o- cells, >300 μM) compared to that of the previous group of pro-AMPs. The bactericidal activity of pro-WMR was increased in NE-rich bronchoalveolar lavage (BAL) fluid from CF patients (range, 8.4% ± 6.9% alone to 91.5% ± 5.8% with BAL fluid; P = 0.0004), an activity differential greater than that of previous pro-AMPs. In a murine model of lung delivery, the pro-AMP modification reduced host toxicity, with pro-WMR being less toxic than the active peptide. Previously, host toxicity issues have hampered the clinical application of AMPs. However, the development of application-specific AMPs with modifications that minimize toxicity similar to those described here can significantly advance their potential use in patients. The combination of this prodrug strategy with a highly active AMP has the potential to produce new therapeutics for the challenging conditions of the CF patient lung.
authors.affiliation: Centre for Synthesis and Chemical Biology, Department of Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in Ireland, Dublin, Ireland Department of Clinical Microbiology, Royal College of Surgeons in Ireland, Dublin, Ireland fordee@tcd.ie.
authors.forename: Éanna
authors.initials: É
authors.lastname: Forde
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), University of Heidelberg, Heidelberg, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Schütte
authors.affiliation: Pulmonary Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
authors.forename: Emer
authors.initials: E
authors.lastname: Reeves
authors.affiliation: Pulmonary Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Greene
authors.affiliation: Department of Clinical Microbiology, Royal College of Surgeons in Ireland, Dublin, Ireland Department of Microbiology, Beaumont Hospital, Dublin, Ireland.
authors.forename: Hilary
authors.initials: H
authors.lastname: Humphreys
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), University of Heidelberg, Heidelberg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Mall
authors.affiliation: Department of Clinical Microbiology, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Deirdre
authors.initials: D
authors.lastname: Fitzgerald-Hughes
authors.affiliation: Centre for Synthesis and Chemical Biology, Department of Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Marc
authors.initials: M
authors.lastname: Devocelle
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity*; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002460:Cell Line; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism* / Q000633:toxicity*; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D011355:Prodrugs