Rationally-designed Multivalent Architectures for Mimicking Homotrimers of CD40L, a Member of the TNF Superfamily

摘要

Ligands and receptors of the TNF superfamilies play a central role in the organization and function of the immune system [1]. Ligands of the TNF-family, share a common structural motif. Monomers self-assemble around a three-fold symmetry axis to form non-covalent homotrimers that can each bind three receptor molecules. Interaction between CD40, a member of the TNF receptor 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.Synthetic multivalent ligands, owing to the presence of multiple copies of a recognition motif attached to a central scaffold, can mediate clustering of cell surface receptors and thereby function as effector molecules [2]. We have shown previously that rigid trimeric scaffolds can serve to distribute a CD40-binding motif with geometry and distances that could match that of the natural CD40L protein (Figure 1) [3,4]. A short sequence from the surface of CD40L, encompassing three "hot-spot" residues (Lysl43, Tyrl45 and Tyrl46) critical for binding to CD40, was chosen as a CD40 binding motif.