Siglecs, a class of immunological checkpoint receptors, are present in all types of immune cells. due to their interaction with various sialoglycan ligands, they send signals to immune cells instructing them whether the target is healthy or wounded, a self or not. The majority of Siglecs are classified as "inhibitory" because they contain intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIM) and ITIM-like motifs in their cytoplasmic tail, whereas a small subset (Siglecs-14, -15, and 16) are "activating," signaling via adaptor proteins like DNAX-activating protein-10 and DNAX-activating protein-12. One class of Siglec agonists that shows promise is synthetic ligands. Many examples (such as sialopolymers, nanoparticles, and liposomes) rely on clustering structures to produce their impact.
Fig.1 Siglec and Siglec ligand. (Jiang, et al., 2021)
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Anti-Siglec antibodies may agonize or impair siglec activity. Siglec-inhibiting antibodies can function as antagonists by preventing ligand binding. Immune cell activation can be decreased and apoptosis can be increased by antibodies that target the siglec agonist. The appropriate Siglec interacts with synthetic Siglec ligands on liposomes or nanoparticles, clustering it and, in certain cases, causing it to localize near an activating receptor and preventing its activation.
COVID-19's viral pathogen-associated molecular patterns and virally-induced cytokines can cause neutrophils to go through NETosis at the site of infection and in the surrounding area. Siglec-9 agonists prevent COVID-19 plasma-induced NETosis, potentially minimizing detrimental hyperinflammatory effects. Recombinant Siglec ligands can act as agonists for the Siglec receptor. Dendritic cell Siglec-10, for instance, reduced responses to damage-related molecular patterns by interacting with CD24. Siglecs can be triggered by agonist antibodies to lower immune cell reactivity when combined with anti-inflammatory drugs.
Researchers developed a lipid-linked glycopolypeptide scaffold (pS9L-lipid) that contains customized Siglec-9 ligand glycans. They observed that pS9L-lipid inserts specifically and in cis bind Siglec-9, which consequently causes Siglec-9 signaling to limit macrophage activity. So a promising therapeutic approach is to inhibit phagocyte activity using membrane-tethered glycopolypeptides.
Fig.2 Lipid-tethered glycopolypeptides cluster and agonize Siglecs in cis on effector cells. (Delaveris, et al., 2021)
Due to the great functions of Siglecs agonists, CD BioGlyco has built a strong and excellent platform to study carbohydrate changes in diseases. if you are interested in our services, please feel free to contact us. We are proud to be able to provide you with timely and effective assistance.
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