Letter abstract

Nature Chemical Biology 1, 377 - 382 (2005)
Published online: 6 November 2005 | doi:10.1038/nchembio746

C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L

Sylvie Fournel1, Sébastien Wieckowski1, Weimin Sun1,5, Nathalie Trouche1, Hélène Dumortier1, Alberto Bianco1, Olivier Chaloin1, Mohammed Habib2, Jean-Christophe Peter1, Pascal Schneider3, Bernard Vray2, René E Toes4, Rienk Offringa4, Cornelis J M Melief4, Johan Hoebeke1 & Gilles Guichard1

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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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  1. UPR 9021 CNRS, Immunologie et Chimie Thérapeutiques, Institut de Biologie Moléculaire et Cellulaire, 15 rue René Descartes, F-67084 Strasbourg Cedex, France.
  2. Laboratoire d'Immunologie Expérimentale (CP 615), Faculté de Médecine, Université Libre de Bruxelles, 808 Route de Lennik, 1070 Brussels, Belgium.
  3. Department of Biochemistry, University of Lausanne, Ch. des Boveresses 155, CH-1066 Epalinges.
  4. Leiden University Medical Center, Department of Immunohaematology and Blood Transfusion, Albinusdreef 2, E3-Q, Postbox 9600, 2300 RC, Leiden, The Netherlands.
  5. Present address: Institute of Biological Science and Technology, Beijing Jiaotong University, 3 Shang Yuan Cun, Haidian District, 100044 Beijing, China.

Correspondence to: Sylvie Fournel1 e-mail: s.fournel@ibmc.u-strasbg.fr

Correspondence to: Gilles Guichard1 e-mail: G.Guichard@ibmc.u-strasbg.fr