Proteolytically Stable Foldamer Mimics of Host-Defense Peptides with Protective Activities in a Murine Model of Bacterial Infection

• Published in: Journal of medicinal chemistry 2016-09, Vol.59 (18), p.8221-8232
• Main Authors: Teyssières, Emilie, Corre, Jean-Philippe, Antunes, Stephanie, Rougeot, Catherine, Dugave, Christophe, Jouvion, Grégory, Claudon, Paul, Mikaty, Guillain, Douat, Céline, Goossens, Pierre L, Guichard, Gilles
• Format: Article
• Language: English
• Subjects: Animals; Anthrax - drug therapy; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacokinetics; Antimicrobial Cationic Peptides - pharmacology; Antimicrobial Cationic Peptides - therapeutic use; Bacillus anthracis - drug effects; Female; Mice; Mice, Inbred BALB C; Models, Molecular; Peptidomimetics - chemistry; Peptidomimetics - pharmacokinetics; Peptidomimetics - pharmacology; Peptidomimetics - therapeutic use; Urea - analogs & derivatives; Urea - pharmacokinetics; Urea - pharmacology; Urea - therapeutic use
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00144

The synthesis of bioinspired unnatural backbones leading to foldamers can provide effective peptide mimics with improved properties in a physiological environment. This approach has been applied to the design of structural mimics of membrane active antimicrobial peptides (AMPs) for which activities in vitro have been reported. Yet activities and pharmacokinetic properties in vivo in animal models have remained largely unexplored. Here, we report helical oligourea AMP mimics that are active in vitro against bacterial forms of Bacillus anthracis encountered in vivo, as well as in vivo in inhalational and cutaneous mouse models of B. anthracis infection. The pharmacokinetic profile and the tissue distribution were investigated by β-radio imager whole-body mapping in mice. Low excretion and recovery of the native oligourea in the kidney following intravenous injection is consistent with high stability in vivo. Overall these results provide useful information that support future biomedical development of urea-based foldamer peptide mimics.