title: Adamantane-based dendrons for trimerization of the therapeutic P140 peptide.
abstract: Dendrons constituted of an adamantane core, a focal point and three arms, were synthetized starting from a multifunctional adamantane derivative. Maleimido groups at the periphery of the scaffold were used to covalently attach the peptide called P140, a therapeutic phosphopeptide controlling disease activity in systemic lupus, both in mice and patients. Biotinylation of the trimers at the focal point was performed using click chemistry and the conjugates were studied in terms of solubility, binding affinity to its receptor, the HSPA8/HSC70 chaperone protein, effect on HSPA8 folding property and in vivo activity. The results showed that the trimerization of P140 peptide does not trigger aggregation or steric hindrances during the interaction with HSPA8 protein. Compared to the monomeric cognate peptide, the trivalent P140 peptide displayed the same capacity, in vitro, to down-regulate HSPA8 activity and, in vivo in MRL/lpr lupus-prone mice, to reduce abnormal blood hypercellularity. The control trimer synthesized with the same scaffold and a scrambled sequence of P140 showed no effect in vivo. This work reveals that adamantane-based scaffolds with a well-defined spatial conformation are promising trivalent systems for molecular recognition and for biomedical applications.
authors.affiliation: CNRS, Institut de Biologie Moléculaire et Cellulaire, Laboratoire d'Immunopathologie et Chimie Thérapeutique, Strasbourg, France.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lamanna
authors.affiliation: CNRS, Institut de Biologie Moléculaire et Cellulaire, Laboratoire d'Immunopathologie et Chimie Thérapeutique, Strasbourg, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Grillaud
authors.affiliation: CNRS, Institut de Biologie Moléculaire et Cellulaire, Laboratoire d'Immunopathologie et Chimie Thérapeutique, Strasbourg, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Macri
authors.affiliation: CNRS, Institut de Biologie Moléculaire et Cellulaire, Laboratoire d'Immunopathologie et Chimie Thérapeutique, Strasbourg, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Chaloin
authors.affiliation: CNRS, Institut de Biologie Moléculaire et Cellulaire, Laboratoire d'Immunopathologie et Chimie Thérapeutique, Strasbourg, France. Electronic address: s.muller@ibmc-cnrs.unistra.fr.
authors.forename: Sylviane
authors.initials: S
authors.lastname: Muller
authors.affiliation: CNRS, Institut de Biologie Moléculaire et Cellulaire, Laboratoire d'Immunopathologie et Chimie Thérapeutique, Strasbourg, France. Electronic address: a.bianco@ibmc-cnrs.unistra.fr.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bianco
mesh_terms: D000218:Adamantane / Q000737:chemistry*; D000818:Animals; D001710:Biotin / Q000737:chemistry; D050091:Dendrimers / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000378:metabolism; D019463:Mice, Inbred MRL lpr; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D050091:Dendrimers; D004337:Drug Carriers; D050883:HSC70 Heat-Shock Proteins; C494372:Hspa8 protein, mouse; D010446:Peptide Fragments; C535176:spliceosomal peptide P140; D001710:Biotin; D000218:Adamantane
keywords: Adamantane; C3-symmetry; Dendrimers; Dendrons; HSPA8 protein; P140 peptide