New Human CD22/Siglec‐2 Ligands with a Triazole Glycoside

Abstract

CD22 is a member of the Siglec family. Considerable attention has been drawn to the design and synthesis of new Siglec ligands to explore target biology and innovative therapies. In particular, CD22‐ligand‐targeted nanoparticles with therapeutic functions have proved successful in preclinical settings for blood cancers, autoimmune diseases, and tolerance induction. Here we report the design, synthesis and affinity evaluation of a new class of Siglec ligands: namely sialic acid derivatives with a triazole moiety replacing the natural glycoside oxygen atom. In addition, we describe important and surprising differences in binding to CD22 expressed at the cell surface for compounds with distinct valences. The new class of compounds might serve as a template for the design of ligands for other members of the Siglec family and next‐generation CD22‐ligand‐based targeted therapies.

Characterisation of the Dynamic Interactions between Complex N‐Glycans and Human CD22

“…These immunoregulatory functions made CD22 an attractive target for therapies against autoimmune diseases and various B‐cell‐derived malignancies including hairy cell leukaemia, marginal zone lymphoma, chronic lymphocytic leukaemia and non‐Hodgkin lymphoma . Thus, deeper molecular insights into the mechanisms that govern sensing of N ‐glycans by CD22 might provide valuable clues to assist the development of new mimetics targeting CD22–glycan interactions.…”

Strategies for the Development of Glycomimetic Drug Candidates

“…For example, Siglec-7 inhibitors have been synthesized which contain C-9 aromatic modifications (also targeting a ‘hydrophobic gate’ observed in the crystal structure) and/or triazole-containing hydrophobic groups at C-2 of Neu5Ac, in an effort to develop inhibitors which could prevent immune evasion by cancer cells (Figure 8) [67,68]. Similar in structure, Siglec-2 (also known as CD22) Neu5Ac glycomimetics containing a C-9 N -aromatic moiety, C-4 N -acyl derivative, and C-2 n -alkyl group have been used as inhibitors and towards drug conjugates to specifically target uptake into specific subsets of immune cells via Siglec-2-binding clathrin-mediated endocytosis (Figure 9) [69,70,71]. Pseudomonas aeruginosa lectin B (LecB) inhibitors have been developed in an effort to tackle biofilm formation: low molecular weight, nanomolar affinity ligands with good kinetic and thermodynamic properties were developed by targeting a hydrophobic patch on the protein [72].…”

Nanotechnology and sialic acid biology

“…CD22 is a member of the Siglec family and CD22-ligand-targeted NPs with therapeutic functions have proved successful in preclinical settings for blood cancers, autoimmune diseases, and tolerance induction [77].…”