title: Chemical optimization of new ligands of the low-density lipoprotein receptor as potential vectors for central nervous system targeting.
abstract: Drug delivery to the central nervous system is hindered by the presence of physiological barriers such as the blood-brain barrier. To accomplish the task of nutrient transport, the brain endothelium is endowed with various transport systems, including receptor-mediated transcytosis (RMT). This system can be used to shuttle therapeutics into the central nervous system (CNS) in a noninvasive manner. Therefore, the low-density lipoprotein receptor (LDLR) is a relevant target for delivering drugs. From an initial phage display biopanning, a series of peptide ligands for the LDLR was optimized leading to size reduction and improved receptor binding affinity with the identification of peptide 22 and its analogues. Further real-time biphoton microscopy experiments on living mice demonstrated the ability of peptide 22 to efficiently and quickly cross CNS physiological barriers. This validation of peptide 22 led us to explore its binding on the extracellular LDLR domain from an NMR-oriented structural study and docking experiments.
authors.affiliation: Institut des Biomolécules Max-Mousseron, UMR5247 CNRS, UFR des Sciences Pharmaceutiques et Biologiques, Universités Montpellier I et II, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France.
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Malcor
authors.forename: Nadine
authors.initials: N
authors.lastname: Payrot
authors.forename: Marion
authors.initials: M
authors.lastname: David
authors.forename: Aude
authors.initials: A
authors.lastname: Faucon
authors.forename: Karima
authors.initials: K
authors.lastname: Abouzid
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jacquot
authors.forename: Nicolas
authors.initials: N
authors.lastname: Floquet
authors.forename: Franck
authors.initials: F
authors.lastname: Debarbieux
authors.forename: Geneviève
authors.initials: G
authors.lastname: Rougon
authors.forename: Jean
authors.initials: J
authors.lastname: Martinez
authors.forename: Michel
authors.initials: M
authors.lastname: Khrestchatisky
authors.forename: Patrick
authors.initials: P
authors.lastname: Vlieghe
authors.forename: Vincent
authors.initials: V
authors.lastname: Lisowski
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D005456:Fluorescent Dyes; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011973:Receptors, LDL / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*; D013329:Structure-Activity Relationship; D057900:Transcytosis
chemical_list: D005456:Fluorescent Dyes; D008024:Ligands; D009842:Oligopeptides; D010456:Peptides, Cyclic; D011973:Receptors, LDL