Pseudosaccharides Functionalized Dendrons Inhibitors of MBL Are Able to Prevent Ischemic Injury In Mice

Recently, it has been demonstrated that the powerful protective effect of recombinant human complement C1-inhibitor (rhC1-INH) in cerebral ischemia is due to its ability to inhibit the activation of complement lectin pathway by binding to mannose binding lectin (MBL),1 likely through its mannose-enriched N-terminal domain. To explore the relevance of the lectin pathway in cerebral ischemia we have determined if newly synthesized mannosylated mimetic molecules, characterized and selected for their binding to MBL, are able to prevent ischemic injury in mice. Multivalent carbohydrate systems are required to interact in an efficient manner with this receptor and compete with the natural ligands. We have previously demonstrated that linear pseudodi- and pseudotrisaccharides are adequate ligands for lectins that recognize mannose, for example, DC-SIGN.2 In this work, we show that multivalent presentations of these glycomimetics based on dendrons lead to very potent inhibitors of MBL and also we indicate that the inhibition of this protein leads to neuroprotection. The affinity of mannosylated molecules to MBL was measured by surface plasmon resonance (SPR). The molecule showing the highest affinity to MBL was administered intravenously to ischemic mice and neurological deficits and infarct volume were evaluated. Polyman002, a dendron exposing four copies of the pseudo-trisaccharide bind MBL with a KD=2.3±0.7μM and induced a significant reduction of neurological deficits and ischemic volume in vivo. Our findings, together with those recently published by Cervera et al.,3 indicate that MBL inhibition may represent a novel therapeutic target for stroke. References 1. Gesuete, R., Storini, C., Fantin, A., Stravalaci, M., Zanier, E.R., Orsini, F., Vietsch, H., Mannessem M.L., Ziere, B., Gobbi, M., De Simoni, M.G., Ann. Neurol., 2009, 66, 332-342. 2. (a) Sattin, S., Daghetti, A., Thépaut, M., Berzi, A., Sánchez-Navarro, M., Tabarani, G., Rojo, J., Fieschi, F., Clerici, M., Bernardi, A., ACS Chem. Biol., 2010, 3, 301-312. (b) Luczkowiak, J., Sattin, S., Reina, J.J., Sánchez-Navarro, M., Sutkevičiūtė, I., Thépaut, M., Martínez-Prats, L., Daghetti, A., Fieschi, F., Delgado, R., Bernardi, A., Rojo. J., unpublished results. 3. Cervera, A., Planas, A.M., Justicia, C., Urra, X., Jensenius, J.C., Torres, F., Lozano, F., Chamorro, A., PLoS One, 2010, 5, e8433.