Preparation of a Multitopic Glycopeptide−Oligonucleotide Conjugate

Abstract

[structure: see text] A novel strategy to prepare glycopeptide-oligonucleotide conjugates bearing a glycocluster is reported. The strategy utilizes a cyclodecapeptide scaffold as a key intermediate to anchor the carbohydrate cluster and the oligonucleotide through sequential oxime bond formation. The oligonucleotide glycocluster retains the binding affinity and recognition specificity for the target sequence. Furthermore, the conjugate shows enhanced binding to the specific lectins due to the cooperative effect produced by the carbohydrate cluster.

Nucleophilic Catalysis of Oxime Ligation

“…[1][2][3][4][5][6][7][8] Aldehydes and ketones can be readily introduced into biomolecules and are virtually inert towards reaction with other functional groups in these molecules. Under acidic conditions the carbonyl group reacts with primary amines to form a reversible imine (Scheme 1 a), and the equilibrium favors the free carbonyl.…”

“…However, when a-effect nitrogens [9] such as aminooxy groups and hydrazides are used, the equilibrium favors the imine. [1][2][3][4][5][6][7][8] Oxime ligations are often called upon to link complex and precious macromolecules. [7,8] The oxime bond is stable under physiological conditions, whereas more dynamic imines, such as hydrazones, are often reduced to obtain a stable linkage.…”

“…Furthermore, aniline is soluble in a range of solvents and can be used as a convenient aqueous buffer with acetic acid, and both its solubility and nucleophilicity can be tuned through the introduction of substituents on the aromatic ring. Aniline catalysis will have a major impact on the numerous applications of imine chemistry including bioconjugation, [1][2][3][4][5][6][7][8] cellular labeling, [18,19] surface immobilization, [20] and dynamic combinatorial libraries. [21,22] .…”

A Fully Solid-Phase Synthesis of Biotinylated Glycoclusters

“…As part of our program related to the evaluation of the interaction between carbohydrates and proteins, we have developed recently a new molecularly well-defined addressable scaffold (Regioselectively Addressable Functionalized Template) [13]. The structural features of this cyclopeptide-based template allow the sequential and regioselective assembly of both biomolecules and any other functional units which provide thereby recognition and effector properties to the molecule [14][15][16][17]. Particularly, we have reported the synthesis of diverse multivalent labeled glycoclusters combined solid-phase and solution convergent strategy [18].…”

Synthesis and Application of Glycopeptide and Glycoprotein Mimetics

“…The relatively low mass of the obtained glycoprotein mimetic 85 (approx. 8 kD) facilitated high-accuracy In a series of papers, the Dumy group explored cyclic peptides with regioselectively addressable side-chain amino groups for the tetravalent presentation of mono-and disaccharides [129][130][131][132]. Recently, they reported the synthesis of a cyclic peptide template with two separated addressable domains (Scheme 17) [131].…”