Targeting Human CD22/Siglec-2 with Dimeric Sialosides as Novel Oligosaccharide Mimetics

Abstract

Significant interest in the development of high-affinity ligands for Siglecs exists due to the various therapeutically relevant functions of these proteins. Here, we report a new strategy to develop and design Siglec ligands as disialyl-oligosaccharide mimetics exemplified on Siglec-2 (CD22). We report insights into development of dimeric ligands with high affinity and avidity to cell surface-expressed CD22, assay development, tool compounds, structure activity relationships, and biological data on calcium flux regulation in B-cells. The binding modes of selected ligands have been modeled based on state-of-the-art molecular dynamics simulations on the microsecond timescale, providing detailed views on ligand binding and opening a new perspective on drug design efforts for Siglecs. High-avidity dimeric ligands containing a linker opening the way towards bispecifics are presented as well.

Synthesis and Binding Mode Predictions of Novel Siglec-7 Ligands

“…We used an MD simulation-based technique developed previously to predict successfully the binding mode of CD22 ligands. 56 MD simulations with an accumulated time scale of 10 μs were performed to allow the flexible glycosidic noncarbohydrate portion of the ligand (termed S2 substituent here) to explore and potentially settle into meaningful binding modes (Figure 4). In order to avoid dissociation of the ligand on such long MD time scales, distance restraints were applied between atom pairs SIA/O1A-R124/NH1, SIA/O1B-R124/ NH2, SIA/N5-K131/O, and SIA/O8-N133/N.…”

“…The starting structure of the complex with ligand 10 was built by extending the truncated version described above. We used an MD simulation-based technique developed previously to predict successfully the binding mode of CD22 ligands . MD simulations with an accumulated time scale of 10 μs were performed to allow the flexible glycosidic noncarbohydrate portion of the ligand (termed S2 substituent here) to explore and potentially settle into meaningful binding modes ( Figure ).…”

Glycomimetics for the inhibition and modulation of lectins

“…However, cross-linking of a cell surface receptor should not be excluded as a viable mechanism route to inhibition as evidenced by dimerization of the Siglec CD22 or the CTL LOX-1. 592,593 In a recent report, carbohydrate-based glycomimetic 173 was designed for langerin to benefit from a biphenyl extending of the anomeric position (Fig. 39).…”

“…However, cross-linking of a cell surface receptor should not be excluded as a viable mechanism route to inhibition as evidenced by dimerization of the Siglec CD22 or the CTL LOX-1. 592,593…”

Convergent Synthesis of a Hexadecavalent Heterobifunctional ABO Blood Group Glycoconjugate

“…License: CC BY-NC-ND 4.0 three copies of a nitrophenyl antigen and three copies of a high-affinity CD22 ligand has been reported, [35] and more recently dimeric CD22 ligands have been developed. [36] Our group has been interested in the development of heterobifunctional glycoconjugates that allow presentation of multiple carbohydrate antigens for controlling receptor organization. Specifically, we developed a heterobifunctional linker that allowed elaboration of a tetravalent PEG scaffold with two carbohydrate ligands: a 6'-sialyl-lactose (6'SL) ligand for CD22, and a human A type II (AII) blood group antigen.…”