title: C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L.
abstract: Interaction between CD40, a member of the tumor necrosis factor receptor (TNFR) superfamily, and its ligand CD40L, a 39-kDa glycoprotein, is essential for the development of humoral and cellular immune responses. Selective blockade or activation of this pathway provides the ground for the development of new treatments against immunologically based diseases and malignancies. Like other members of the TNF superfamily, CD40L monomers self-assemble around a threefold symmetry axis to form noncovalent homotrimers that can each bind three receptor molecules. Here, we report on the structure-based design of small synthetic molecules with C3 symmetry that can mimic CD40L homotrimers. These molecules interact with CD40, compete with the binding of CD40L to CD40, and reproduce, to a certain extent, the functional properties of the much larger homotrimeric soluble CD40L. Architectures based on rigid C3-symmetric cores may thus represent a general approach to mimicking homotrimers of the TNF superfamily.
authors.affiliation: UPR 9021 CNRS, Immunologie et Chimie Thérapeutiques, Institut de Biologie Moléculaire et Cellulaire, 15 rue René Descartes, F-67084 Strasbourg, France. s.fournel@ibmc.u-strasbg.fr
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fournel
authors.forename: Sébastien
authors.initials: S
authors.lastname: Wieckowski
authors.forename: Weimin
authors.initials: W
authors.lastname: Sun
authors.forename: Nathalie
authors.initials: N
authors.lastname: Trouche
authors.forename: Hélène
authors.initials: H
authors.lastname: Dumortier
authors.forename: Alberto
authors.initials: A
authors.lastname: Bianco
authors.forename: Olivier
authors.initials: O
authors.lastname: Chaloin
authors.forename: Mohammed
authors.initials: M
authors.lastname: Habib
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Peter
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.forename: Bernard
authors.initials: B
authors.lastname: Vray
authors.forename: René E
authors.initials: RE
authors.lastname: Toes
authors.forename: Rienk
authors.initials: R
authors.lastname: Offringa
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
authors.forename: Johan
authors.initials: J
authors.lastname: Hoebeke
authors.forename: Gilles
authors.initials: G
authors.lastname: Guichard
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019013:CD40 Antigens / Q000096:biosynthesis / Q000737:chemistry / Q000187:drug effects*; D023201:CD40 Ligand / Q000737:chemistry / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D018716:Molecular Mimicry / Q000187:drug effects*; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D019013:CD40 Antigens; D010455:Peptides; D023201:CD40 Ligand