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Volume 271, Number 45, Issue of November 8, 1996 pp. 28024-28030
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Lysine-based Cluster Mannosides That Inhibit Ligand Binding to the Human Mannose Receptor at Nanomolar Concentration

(Received for publication, April 18, 1996, and in revised form, August 19, 1996)

Erik A. L. Biessen , Femke Noorman ^¶ , Marco E. van Teijlingen , Johan Kuiper , Marrie Barrett-Bergshoeff ^¶ , Martin K. Bijsterbosch , Dingeman C. Rijken ^¶ and Theo J. C. van Berkel

From the  Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, University of Leiden, P.O. Box 9503, 2300 RA Leiden, The Netherlands and the ^¶ Gaubius Laboratory, TNO Prevention and Health, P.O. Box 2215, 2301 CE Leiden, The Netherlands

In search of synthetic high affinity ligands for the mannose receptor, we synthesized a series of lysine-based oligomannosides containing two (M₂L) to six (M₆L₅) terminal -D-mannose groups that are connected with the backbone by flexible elongated spacers (16 Å). The synthesized cluster mannosides were all able to displace binding of biotinylated ribonuclease B and tissue-type plasminogen activator to isolated human mannose receptor. The affinity of these cluster mannosides for the mannose receptor was continuously enhanced from 18-23 µM to 0.5-2.6 nM, with mannose valencies increasing from two to six. On average, expansion of the cluster mannoside with an additional -D-mannose group resulted in a 10-fold increase in its affinity for the mannose receptor. M₃L₂ to M₆L₅ displayed negative cooperative inhibition of ligand binding to the mannose receptor, suggesting that binding of these mannosides involves multiple binding sites. The nanomolar affinity of the most potent ligand, the hexamannoside M₆L₅ makes it the most potent synthetic cluster mannoside for the mannose receptor yet developed. As a result of its high affinity and accessible synthesis, M₆L₅ not only is a powerful tool to study the mechanism of ligand binding by the mannose receptor, but it is also a promising targeting device to accomplish cell-specific delivery of genes and drugs to liver endothelial cells or macrophages in bone marrow, lungs, spleen, and atherosclerotic plaques.

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