C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L.
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.
Fournel
Sylvie
S
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
Wieckowski
Sébastien
S
Sun
Weimin
W
Trouche
Nathalie
N
Dumortier
Hélène
H
Bianco
Alberto
A
Chaloin
Olivier
O
Habib
Mohammed
M
Peter
Jean-Christophe
JC
Schneider
Pascal
P
Vray
Bernard
B
Toes
René E
RE
Offringa
Rienk
R
Melief
Cornelis J M
CJ
Hoebeke
Johan
J
Guichard
Gilles
G
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
D019013:CD40 Antigens; D010455:Peptides; D023201:CD40 Ligand