title: Carbohydrate-lectin recognition of sequence-defined heteromultivalent glycooligomers.
abstract: Multivalency as a key principle in nature has been successfully adopted for the design and synthesis of artificial glycoligands by attaching multiple copies of monosaccharides to a synthetic scaffold. Besides their potential in various applied areas, e.g. as antiviral drugs, for the vaccine development and as novel biosensors, such glycomimetics also allow for a deeper understanding of the fundamental aspects of multivalent binding of both artificial and natural ligands. However, most glycomimetics so far neglect the purposeful arranged heterogeneity of their natural counterparts, thus limiting more detailed insights into the design and synthesis of novel glycomimetics. Therefore, this work presents the synthesis of monodisperse glycooligomers carrying different sugar ligands at well-defined positions along the backbone using for the first time sequential click chemistry and stepwise assembly of functional building blocks on solid support. This approach allows for straightforward access to sequence-defined, multivalent glycooligomers with full control over number, spacing, position, and type of sugar ligand. We demonstrate the synthesis of a set of heteromultivalent oligomers presenting mannose, galactose, and glucose residues. All heteromultivalent structures show surprisingly high affinities toward Concanavalin A lectin receptor in comparison to their homomultivalent analogues presenting the same number of binding ligands. Detailed studies of the ligand/receptor interaction using STD-NMR and 2fFCS indeed indicate a change in binding mechanism for trivalent glycooligomers presenting mannose or combinations of mannose and galactose residues. We find that galactose residues do not participate in the binding to the receptor, but they promote steric shielding of the heteromultivalent glycoligands and thus result in an overall increase in affinity. Furthermore, the introduction of nonbinding ligands seems to suppress receptor clustering of multivalent ligands. Overall these results support the importance of heteromultivalency specifically for the design of novel glycoligands and help to promote a fundamental understanding of multivalent binding modes.
authors.affiliation: Max Planck Institute of Colloids and Interfaces, Research Campus Golm , Am Mühlenberg 1, 14424 Potsdam, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Ponader
authors.forename: Pauline
authors.initials: P
authors.lastname: Maffre
authors.forename: Jonas
authors.initials: J
authors.lastname: Aretz
authors.forename: Daniel
authors.initials: D
authors.lastname: Pussak
authors.forename: Nina M
authors.initials: NM
authors.lastname: Ninnemann
authors.forename: Stephan
authors.initials: S
authors.lastname: Schmidt
authors.forename: Peter H
authors.initials: PH
authors.lastname: Seeberger
authors.forename: Christoph
authors.initials: C
authors.lastname: Rademacher
authors.forename: G Ulrich
authors.initials: GU
authors.lastname: Nienhaus
authors.forename: Laura
authors.initials: L
authors.lastname: Hartmann
mesh_terms: D001665:Binding Sites; D002240:Carbohydrate Sequence; D003208:Concanavalin A / Q000737:chemistry*; D005690:Galactose / Q000737:chemistry*; D005947:Glucose / Q000737:chemistry*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008358:Mannose / Q000737:chemistry*; D009844:Oligosaccharides / Q000138:chemical synthesis* / Q000737:chemistry*; D013499:Surface Properties
chemical_list: D008024:Ligands; D009844:Oligosaccharides; D003208:Concanavalin A; D005947:Glucose; D008358:Mannose; D005690:Galactose