Design and synthesis of a multivalent homing device for targeting to murine CD22

Citation
Lajm. Sliedregt et al., Design and synthesis of a multivalent homing device for targeting to murine CD22, BIO MED CH, 9(1), 2001, pp. 85-97
Citations number
35
Categorie Soggetti
Chemistry & Analysis
Journal title
BIOORGANIC & MEDICINAL CHEMISTRY
ISSN journal
09680896 → ACNP
Volume
9
Issue
1
Year of publication
2001
Pages
85 - 97
Database
ISI
SICI code
0968-0896(200101)9:1<85:DASOAM>2.0.ZU;2-A
Abstract
CD22 is a cell-surface glycoprotein uniquely located on mature B-cells and B-cell derived tumour cells. Current evidence suggests that binding of endo genous ligands to CD22 leads to modulation of B-cell activation by antigen. Incidentally, however, B-cell activation may derail, and lead to an undesi red immune response, for example in cases of allergy, rheumatoid arthritis and Crohn's disease. In this situation, synthetic high-affinity ligands for CD22 may be of therapeutic value as inhibitors of B-cell activation. Recen t studies have revealed that natural ligands for CD22 contain the trisaccha ride NeuAc alpha -2,6-Lac as the basic binding motif. In addition, it has b een demonstrated that binding to CD22 is strongly enhanced by multivalent p resentation of the basic binding motif (cluster effect). In this paper, the stepwise development of a novel multivalent high-affinity ligand for CD22 is described. In the first stage, a series of monovalent NeuAc alpha -2,6-G lc(Y)X type binding motifs was prepared, and their affinity for murine CD22 was monitored, to obtain more insight into the effect of separate structur e elements on ligand recognition. In the second stage, we prepared a trival ent cluster, based on the monovalent motif that displayed the highest affin ity for CD22, NeuAccc2,6-GlcNBzNO(2)OMe (7). This cluster, TRIS(NeuAc alpha -2,6-GlcNBzNO(2))(3) (52), displayed a more than 58-fold higher affinity f or CD22 than the reference structure NeuAc alpha -2,6-LacOMe (10). To our k nowledge, the cluster 52 is one of the most potent antagonists for CD22, ye t synthesised. (C) 2000 Elsevier Science Ltd. All rights reserved.