Selective targeting of C-type Lectin receptors with multivalent glycomimetic antagonists

Mannose-binding lectins (MBL) are soluble mammalian receptors that play a key role in the innate immune system. They recognize cell-surface oligosaccharide patterns of a wide range of pathogens and trigger defensive mechanisms against infection through lectin-pathway complement activation1. Recently, it was found that MBL also recognize different self-altered structures extending their function from innate host defense to generic modulation of inflammatory processes. In particular, recent studies suggest that MBL play a major role in the pathophysiology of ischemia reperfusion and have emerged as potential new targets for stroke treatment2. Our group, in collaboration with MariaGrazia De Simoni (Mario Negri Institute, Milano), has recently demonstrated that a polyester dendrimeric core decorated with four copies of a glycomimetic pseudo-trimannoside ligand (Polyman 2) was able to bind MBL with dissociation constant in the low micromolar range in Surface Plasmon Resonance (SPR) binding assays. In addition, Polyman 2 induced a significant reduction of neurological deficits and ischemic volume after ischemic injury with a unexpected wide therapeutic window in mice-model in vivo assay.3 Here we present a panel of multivalent glycomimetic compounds prepared with the aim to optimize MBL-ligands by improving both the nature of the monovalent ligand and the type of presentation. In particular, we synthesized different ligands in which a pseudo-dimannoside, more synthetically accessible than the pseudo-trimannoside previously reported, was presented by dendrimeric scaffolds with different flexibility and valency. The interaction of these compounds with human MBL, as well as with Ficoline-III to evaluate the binding selectivity, was characterized by SPR. The results will be shown in the presentation. Acknowledgement This work was supported by Fondazione Cariplo (contract 2009-2630), Ministero della Salute (Bando Giovani ricercatori 2008, GR-2008-1136044), COST Action CM1102 (Multiglyconano) Literature 1. Eddie Ip, W. K., Takahashi, K., Alan Ezekowitz, R., Stuart, L. M., Immunological Reviews 2009, 230 (1), 9-21. 2. Gesuete, R., Storini, C., Fantin, A., Stravalaci, M.; Zanier, E. R., Orsini, F.; Vietsch, H., Mannesse, M. L. M., Ziere, B., Gobbi, M., De Simoni, M.-G., Annals of Neurology 2009, 66 (3), 332-342. 3. Orsini, F., Villa, P., Parrella, S., Zangari, R., Zanier, E. R., Gesuete, R., Stravalaci, M., Fumagalli, S., Ottria, R., Reina, J. J., Paladini, A., Micotti, E., Ribeiro-Viana, R., Rojo, J., Pavlov, V. I., Stahl, G. L., Bernardi, A., Gobbi, M., De Simoni, M.-G., Circulation 2012, 126 (12), 1484-1494.