title: Macrocyclic cell penetrating peptides: a study of structure-penetration properties.
abstract: Arginine-rich cell penetrating peptides are short cationic peptides able to cross biological membranes despite their peptidic character. In order to optimize their penetration properties and further elucidate their mechanisms of cellular entry, these peptides have been intensively studied for the last two decades. Although several parameters are simultaneously involved in the internalization mechanism, recent studies suggest that structural modifications influence cellular internalization. Particularly, backbone rigidification, including macrocyclization, was found to enhance proteolytic stability and cellular uptake. In the present work, we describe the synthesis of macrocyclic arginine-rich cell penetrating peptides and study their cellular uptake properties using a combination of flow cytometry and confocal microscopy. By varying ring size, site of cyclization, and stereochemistry of the arginine residues, we studied their structure-uptake relationship and showed that the mode and site of cyclization as well as the stereochemistry influence cellular uptake. This study led to the identification of a hepta-arginine macrocycle as efficient as its linear nona-arginine congener to enter cells.
authors: †Institut de Pharmacologie de Sherbrooke, Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences and ‡Biophotonics Core Facility, Centre de Recherche du Centre Hospitalier, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada.
authors: Hassan
authors: H
authors: Traboulsi
authors: †Institut de Pharmacologie de Sherbrooke, Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences and ‡Biophotonics Core Facility, Centre de Recherche du Centre Hospitalier, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada.
authors: Heidi
authors: H
authors: Larkin
authors: †Institut de Pharmacologie de Sherbrooke, Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences and ‡Biophotonics Core Facility, Centre de Recherche du Centre Hospitalier, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada.
authors: Marc-André
authors: MA
authors: Bonin
authors: †Institut de Pharmacologie de Sherbrooke, Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences and ‡Biophotonics Core Facility, Centre de Recherche du Centre Hospitalier, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada.
authors: Leonid
authors: L
authors: Volkov
authors: †Institut de Pharmacologie de Sherbrooke, Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences and ‡Biophotonics Core Facility, Centre de Recherche du Centre Hospitalier, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada.
authors: Christine L
authors: CL
authors: Lavoie
authors: †Institut de Pharmacologie de Sherbrooke, Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences and ‡Biophotonics Core Facility, Centre de Recherche du Centre Hospitalier, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada.
authors: Éric
authors: É
authors: Marsault
mesh_terms: D002462:Cell Membrane / Q000378:metabolism*; D057846:Cell-Penetrating Peptides / Q000737:chemistry* / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: D057846:Cell-Penetrating Peptides