title: Proteolytically Stable Foldamer Mimics of Host-Defense Peptides with Protective Activities in a Murine Model of Bacterial Infection.
abstract: 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.
authors.affiliation: Pathogénie des Toxi-Infections Bactériennes, Institut Pasteur , 28 rue du Docteur Roux, 75724 Paris, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Teyssières
authors.affiliation: Pathogénie des Toxi-Infections Bactériennes, Institut Pasteur , 28 rue du Docteur Roux, 75724 Paris, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Corre
authors.affiliation: Univ. Bordeaux , CBMN, UMR 5248, Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, 33607 Pessac, France.|CNRS , CBMN, UMR 5248, F-33600 Pessac, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Antunes
authors.affiliation: Laboratoire de Pharmacologie de la Douleur, Institut Pasteur , 28 rue du Docteur Roux, 75724 Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Rougeot
authors.affiliation: Institut de Biologie et de Technologie de Saclay (iBiTec-S), Service de Chimie Bio-organique et de Marquage, CEA-Saclay , bâtiment 547, 91191 Gif-sur-Yvette, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Dugave
authors.affiliation: Institut Pasteur , Histopathologie Humaine et Modèles Animaux, 75724 Paris, France.|Paris Descartes Université , PRES Sorbonne-Paris-Cité, 75006 Paris, France.
authors.forename: Grégory
authors.initials: G
authors.lastname: Jouvion
authors.affiliation: Univ. Bordeaux , CBMN, UMR 5248, Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, 33607 Pessac, France.|CNRS , CBMN, UMR 5248, F-33600 Pessac, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Claudon
authors.affiliation: Pathogénie des Toxi-Infections Bactériennes, Institut Pasteur , 28 rue du Docteur Roux, 75724 Paris, France.
authors.forename: Guillain
authors.initials: G
authors.lastname: Mikaty
authors.affiliation: Univ. Bordeaux , CBMN, UMR 5248, Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, 33607 Pessac, France.|CNRS , CBMN, UMR 5248, F-33600 Pessac, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Douat
authors.affiliation: Pathogénie des Toxi-Infections Bactériennes, Institut Pasteur , 28 rue du Docteur Roux, 75724 Paris, France.|Institut Pasteur , Histopathologie Humaine et Modèles Animaux, 75724 Paris, France.
authors.forename: Pierre L
authors.initials: PL
authors.lastname: Goossens
authors.affiliation: Univ. Bordeaux , CBMN, UMR 5248, Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, 33607 Pessac, France.|CNRS , CBMN, UMR 5248, F-33600 Pessac, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Guichard
mesh_terms: D000818:Animals; D000881:Anthrax / Q000188:drug therapy*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001408:Bacillus anthracis / Q000187:drug effects*; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D057786:Peptidomimetics / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D014508:Urea / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D057786:Peptidomimetics; D014508:Urea