Chemical Synthesis and Evaluation of a Disialic Acid‐Containing Dextran Polymer as an Inhibitor for the Interaction between Siglec 7 and Its Ligand. (5th May 2017)

• Record Type: Journal Article
• Authors: Yamaguchi, Sho; Yoshimura, Atsushi; Yasuda, Yu; Mori, Airi; Tanaka, Hiroshi; Takahashi, Takashi; Kitajima, Ken; Sato, Chihiro
• Is Part Of: Chembiochem. Volume 18:Number 13(2017)
• Page Start: 1194
• Page End: 1203
• Publication Date: 2017-05-05
• Subjects: glycopolymers -- inhibitors -- NK cells -- sialic acid -- Siglec; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201600694
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: A new sialic acid (Sia)‐containing glycopolymer—a fluorescent probe with high‐density disialic acid (diSia) on the surface of polysaccharide dextran (diSia‐Dex)—was synthesized as a key molecule to regulate the Sia recognition lectins, Siglecs, that are involved in the immune system. According to our original methods, diSia was synthesized by α‐selective sialylation, and a dextran template possessing terminal acetylenes and amino groups was prepared. A diSia and a fluorescent molecule were subsequently introduced to surface‐modified dextran by Hüisgen reaction and amidation, respectively. The modulatory activity of Siglec7 was evaluated by using synthetic probes. DiSia‐Dex showed high binding avidity toward Siglec7, with a K D value of 5.87×10 −10 m, and a high inhibitory activity for the interaction between Siglec7 and a ligand (GD3), with a IC50 value of 1.0 nm . Notably, diSia‐Dex was able to release Siglec7 from the pre‐existing Siglec7–GD3 complex, possibly due to its unique properties of a slow dissociation rate and a high association rate. Together, these data show that diSia‐Dex can be widely applicable as a modulator of Siglec7 functions. Abstract : Siglec not ready to mingle : A disialic acid‐containing glycopolymer with a dextran backbone was synthesized by α‐selective sialylation with a dextran template possessing terminal acetylenes and amino groups. This glycopolymer proved to be an effective inhibitor of interactions between Siglec7 and one of its ligands, thus showing that this type of molecule might have applications in modulating Siglec functions.