Scaffold optimization of tetravalent C-lectin antagonists

In recent years our group, in collaboration with the Rojo group (Glycosystems Laboratory, IIQ-CSIC, Sevilla), has demonstrated that tetravalent polyester dendrimers[1] functionalised with glycomimetic pseudo-dimannoside and pseudo-trimannoside ligands work as good inhibitors of the C-type lectins DC-SIGN[1] and MBL[2]. MBL is a circulating C-type lectin that has crucial role in first line of host defense. MBL recognizes polyglycosylated cell surfaces present both on pathogens and self damaged cells and has great importance in the activation of complement, promotion of opsonophagocytosis, promotion of apoptosis and also modulation of inflammation.[3] Recent studies have shown that the capability of MBL in generating an inflammatory environment may be a main cause of the reperfusion damage that occurs after a stroke event, highlighting MBL as a promising target for this pathology.[2,4] The antagonists that we developed so far are able to bind MBL with dissociation constant in the low micromolar range (SPR binding assays). Moreover, the inhibitor 1 bearing as a ligand the pseudo-trimannoside 2 (Figure 1) was tested in vivo and showed a great capability of reducing the ischemic volume in mice with an uncommon wide therapeutic window.[2] The main drawback of this construct consists in its limited half-life in plasma, due to the instability of the succinyl ester which also determines the chromatographic lability of the dendron. Here we present an attempt in the optimization of this scaffold. We are particularly interested in obtaining a product that is still soluble in water and no longer sensitive to hydrolysis and therefore characterised by easier purification procedures and chemical and enzymatic stability. Our results will be shown in the poster. References: 1. J. Luczkowiak, S. Sattin, I. Sutkecičiūtė, J. J. Reina, M. Sánchez-Navarro, M. Thépaut, L. Martínez-Prats, A. Daghetti, F. Fieschi, R. Delgado, A. Bernardi, J. Rojo Bioconjugate Chem. 2011, 22, 1354. 2. F. Orsini, P. Villa, S. Parrella, R. Zangari, E. R. Zanier, R. Gesuete, M. Stravalaci, S. Fumagalli, R. Ottria, J. J. Reina, A. Paladini, E. Micotti, R. Ribeiro-Viana, J. Rojo, V. I. Pavlov, G. L. Stahl, A. Bernardi, M. Gobbi, M.-G. De Simoni Circulation 2012, 126, 1484. 3. M. W. Turner Molecular Immunology 2003, 40, 423; b) A. Cervera, A. M. Planas, C. Justicia, X.Urra, J. C. Jensenius, F. Torres, F. Lozano, A. Chamorro PLOS ONE 2010, 5, e8433. 4. R. Gesuete, C. Storini, A. Fantin, M. Stravalaci, E. R. Zanier, F. Orsini, H. Vietsch, M. L. M. Mannesse, B. Ziere, M. Gobbi, M.-G. De Simoni Annals of Neurology 2009, 66, 332.