title: Scaffold Optimisation of Tetravalent Antagonists of the Mannose Binding Lectin.
abstract: Antagonists of mannose binding lectin (MBL) have shown a protective role against brain reperfusion damage after acute ischemic stroke. Here we describe the design and streamlined synthesis of glycomimetic MBL antagonists based on a new tetravalent dendron scaffold. The dendron was developed by optimisation of a known polyester structure previously demonstrated to be very efficient for ligand presentation to MBL. Replacement of a labile succinyl ester bond with a more robust amide functionality, use of a longer and more hydrophilic linker, fast modular synthesis and orthogonal functionalisation at the focal point are the main features of the new scaffold. The glycoconjugate constructs become stable to silica gel chromatography and to water solutions at physiological pH, while preserving water solubility and activity in an SPR assay against the murine MBL-C isoform. Higher-order constructs were easily assembled, as demonstrated by the synthesis of a 16-valent dendrimer, which leads to two orders of magnitude increase in activity over the tetravalent version against MBL-C.
authors.affiliation: Department of Chemistry, Universita' degli Studi di Milano, via Golgi 19, 20133, Milano, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Goti
authors.affiliation: Department of Chemistry, Universita' degli Studi di Milano, via Golgi 19, 20133, Milano, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Palmioli
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milano, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Stravalaci
authors.affiliation: Department of Chemistry, Universita' degli Studi di Milano, via Golgi 19, 20133, Milano, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Sattin
authors.affiliation: Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milano, Italy.
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: De Simoni
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.affiliation: Department of Chemistry, Universita' degli Studi di Milano, via Golgi 19, 20133, Milano, Italy. anna.bernardi@unimi.it.
authors.forename: Anna
authors.identifier: http://orcid.org/0000-0002-1258-2007
authors.initials: A
authors.lastname: Bernardi
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D050091:Dendrimers / Q000737:chemistry*; D006001:Glycoconjugates / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D037601:Mannose-Binding Lectin / Q000172:deficiency* / Q000502:physiology; D051379:Mice; D020521:Stroke / Q000473:pathology*
chemical_list: D050091:Dendrimers; D006001:Glycoconjugates; D008024:Ligands; D037601:Mannose-Binding Lectin
keywords: glycodendrimers; glycomimetics; mannose binding lectin; multivalency; surface plasmon resonance