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C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L

Nature Chemical Biology volume 1, pages 377–382 (2005)Cite this article

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 responses1,2. Selective blockade or activation of this pathway provides the ground for the development of new treatments against immunologically based diseases3,4 and malignancies5,6. 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 molecules7,8. 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.

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Figure 1: Synthetic C3-symmetric CD40L mimetics.
Figure 2: SPR experiments using hCD40:mIg.
Figure 3: CD40L mimetics induce apoptosis of Burkitt lymphoma cells and colocalize with endogenous CD40.
Figure 4: Effect of 1 on various mouse cells.

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Acknowledgements

We thank J.-P. Briand and S. Muller for support; J. Mutterer for assistance with confocal microscopy; N. Bonnefoy-Berard and M. Flacher for providing Burkitt lymphoma cells and M. Monestier for providing LG11-2 mAb. This work was supported by the Centre National de la Recherche Scientifique, the Ministère de la Recherche (ACI Jeunes Chercheurs), La Ligue contre le Cancer, Région Alsace and the Agence Nationale de Recherches contre le SIDA. S.W. was supported by a grant from the Ministère de la Recherche. W.S. was supported by the Ministère de la Recherche and the Fondation pour la Recherche Médicale. N.T. was supported by La Ligue Contre le Cancer.

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  1. Weimin Sun

    Present address: Institute of Biological Science and Technology, Beijing Jiaotong University, 3 Shang Yuan Cun, Haidian District, 100044, Beijing, China

Authors and Affiliations

  1. UPR 9021 CNRS, Immunologie et Chimie Thérapeutiques, Institut de Biologie Moléculaire et Cellulaire, 15 rue René Descartes, Strasbourg, F-67084, Cedex, France

    Sylvie Fournel, Sébastien Wieckowski, Weimin Sun, Nathalie Trouche, Hélène Dumortier, Alberto Bianco, Olivier Chaloin, Jean-Christophe Peter, Johan Hoebeke & Gilles Guichard

  2. Laboratoire d'Immunologie Expérimentale (CP 615), Faculté de Médecine, Université Libre de Bruxelles, 808 Route de Lennik, Brussels, 1070, Belgium

    Mohammed Habib & Bernard Vray

  3. Department of Biochemistry, University of Lausanne, Ch. des Boveresses 155, CH-1066 Epalinges,

    Pascal Schneider

  4. Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, E3-Q, Postbox 9600, Leiden, 2300 RC, The Netherlands

    René E Toes, Rienk Offringa & Cornelis J M Melief

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Correspondence to Sylvie Fournel.

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Supplementary information

Supplementary Fig. 1

Binding of anti-human CD40 mAb 5C3 to CD40 does not prevent subsequent binding of 1 or hCD40L:CD8 as seen by SPR experiments. (PDF 149 kb)

Supplementary Fig. 2

Scanning single amino acid substitutions within the CD40 binding motif of 1. (PDF 84 kb)

Supplementary Fig. 3

Compound 11, a biotinylated analog of ligand 2 binds to CD40, induces lymphoma apoptosis and interacts with membrane-associated CD40 molecule. (PDF 46 kb)

Supplementary Fig. 4

Maturation of the murine dendritic cell line D1 by CD40L mimetics. (PDF 138 kb)

Supplementary Fig. 5

Preparation and characterization of CD40L mimetic 1. (PDF 117 kb)

Supplementary Table 1

Summary of inhibition experiments and measured kinetic values for the interaction of the different ligands with CD40. (PDF 83 kb)

Supplementary Methods (DOC 78 kb)

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Fournel, S., Wieckowski, S., Sun, W. et al. C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L. Nat Chem Biol 1, 377–382 (2005). https://doi.org/10.1038/nchembio746

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