Synthesis and biological evaluation of 9- N -oxamyl sialosides as Siglec-7 ligands

Prescher, Horst; Gütgemann, Stephan; Frank, Martin; Kuhfeldt, Elena; Watzl, Carsten; Brossmer, Reinhard

doi:10.1016/j.bmc.2015.06.069

Cited by 10 publications

(17 citation statements)

References 66 publications

(66 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In order to elaborate our glycopolypeptide scaffold, we combined the enzymatic methods from Chen and coworkers (35) that we have used previously (36) with the sialic acid analogs previously reported by Paulson and coworkers to bind specific Siglecs with high affinity and selectivity (26). High-affinity Siglec ligands achieved by derivatizing sialic acids at the C5 and/or C9 positions have been previously reported (26,(37)(38)(39)(40)(41)(42). These ligands have monomeric dissociation constants in the low micromolar to single-digit nanomolar range (37).…”

Section: Significancementioning

confidence: 99%

Modulation of immune cell reactivity with cis -binding Siglec agonists

Delaveris

Chiu

Riley

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Inflammatory pathologies caused by phagocytes lead to numerous debilitating conditions, including chronic pain and blindness due to age-related macular degeneration. Many members of the sialic acid-binding immunoglobulin-like lectin (Siglec) family are immunoinhibitory receptors whose agonism is an attractive approach for antiinflammatory therapy. Here, we show that synthetic lipid-conjugated glycopolypeptides can insert into cell membranes and engage Siglec receptors in cis, leading to inhibitory signaling. Specifically, we construct a cis-binding agonist of Siglec-9 and show that it modulates mitogen-activated protein kinase (MAPK) signaling in reporter cell lines, immortalized macrophage and microglial cell lines, and primary human macrophages. Thus, these cis-binding agonists of Siglecs present a method for therapeutic suppression of immune cell reactivity.

show abstract

Section: Significancementioning

confidence: 99%

Modulation of immune cell reactivity with cis -binding Siglec agonists

Delaveris

Chiu

Riley

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Further modifications in multiple positions generated sialosides with much higher affinity to CD22 (2 nM) ( 7 – 10 ). Efficient synthesis of modified sialosides and selection resulted in development of high-affinity synthetic ligands of other Siglecs, such as Siglec-1 ( 11 ), MAG ( 12 ), and Siglec-7 ( 13 , 14 ). Multimers of high-affinity sialoside ligands and nanoparticles carrying these sialosides were developed to target various molecules such as toxins and antigens to Siglecs.…”

Section: Introductionmentioning

confidence: 99%

CD22-Binding Synthetic Sialosides Regulate B Lymphocyte Proliferation Through CD22 Ligand-Dependent and Independent Pathways, and Enhance Antibody Production in Mice

et al. 2018

View full text Add to dashboard Cite

Sialic acid-binding immunoglobulin-like lectins (Siglecs) are expressed in various immune cells and most of them carry signaling functions. High-affinity synthetic sialoside ligands have been developed for various Siglecs. Therapeutic potentials of the nanoparticles and compounds that contain multiple numbers of these sialosides and other reagents such as toxins and antigens have been demonstrated. However, whether immune responses can be regulated by monomeric sialoside ligands has not yet been known. CD22 (also known as Siglec-2) is an inhibitory molecule preferentially expressed in B lymphocytes (B cells) and is constitutively bound and functionally regulated by α2,6 sialic acids expressed on the same cell (cis-ligands). Here, we developed synthetic sialosides GSC718 and GSC839 that bind to CD22 with high affinity (IC50 ~100 nM), and inhibit ligand binding of CD22. When B cells are activated by B cell antigen receptor (BCR) ligation, both GSC718 and GSC839 downregulate proliferation of B cells, and this regulation requires both CD22 and α2,6 sialic acids. This result suggests that these sialosides regulate BCR ligation-induced B cell activation by reversing endogenous ligand-mediated regulation of CD22. By contrast, GSC718 and GSC839 augment B cell proliferation induced by TLR ligands or CD40 ligation, and this augmentation requires CD22 but not α2,6 sialic acids. Thus, these sialosides appear to enhance B cell activation by directly suppressing the inhibitory function of CD22 independently of endogenous ligand-mediated regulation. Moreover, GSC839 augments B cell proliferation that depends on both BCR ligation and CD40 ligation as is the case for in vivo B cell responses to antigens, and enhanced antibody production to the extent comparable to CpG oligonuleotides or a small amount of alum. Although these known adjuvants induce production of the inflammatory cytokines or accumulation of inflammatory cells, CD22-binding sialosides do not. Thus, synthetic sialosides that bind to CD22 with high-affinity modulate B cell activation through endogenous ligand-dependent and independent pathways, and carry an adjuvant activity without inducing inflammation.

show abstract

“…A range of different ligands, including natural ones like gangliosides, oligosaccharides, and modified sialic acids have been identified, but so far, no soluble, monovalent Siglec-7 ligands have been shown to have sufficient affinity to allow investigation of their effect on Siglec-7 functions. ,− Nature compensates the low affinity of many lectins, including Siglec-7, with increased avidity obtained by polyvalent display of their ligands. , No generally applicable approach to mimic the complex spatial and flexible display of natural, glycocalix-associated low-affine but polyvalent ligands has been described. A few reports elegantly solved the challenge of mimicking natural, polyvalent display of Siglec-7 ligands to investigate specific functions of the protein. ,, Results from these studies together with additional medical, biological, and biochemical data provide strong evidence that Siglec-7 plays a role in cancer immune evasion. ,,− ,− We aimed to develop soluble, monovalent high-affinity ligands to explore their effect on Siglec-7, especially since the effect of monovalent, low molecular weight compounds might be completely different compared to polyvalent ligands or antibodies.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Small, High-Affinity Siglec-7 Ligands: Toward Novel Inhibitors of Cancer Immune Evasion

Prescher

Frank

Gütgemann³

et al. 2017

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

Natural killer cells are able to directly lyse tumor cells, thereby participating in the immune surveillance against cancer. Unfortunately, many cancer cells use immune evasion strategies to avoid their eradication by the immune system. A prominent escape strategy of malignant cells is to camouflage themselves with Siglec-7 ligands, thereby recruiting the inhibitory receptor Siglec-7 expressed on the NK cell surface which subsequently inhibits NK-cell-mediated lysis. Here we describe the synthesis and evaluation of the first, high-affinity low molecular weight Siglec-7 ligands to interfere with cancer cell immune evasion. The compounds are Sialic acid derivatives and bind with low micromolar K values to Siglec-7. They display up to a 5000-fold enhanced affinity over the unmodified sialic acid scaffold αMe Neu5Ac, the smallest known natural Siglec-7 ligand. Our results provide a novel immuno-oncology strategy employing natural immunity in the fight against cancers, in particular blocking Siglec-7 with low molecular weight compounds.

show abstract

Synthesis and biological evaluation of 9- N -oxamyl sialosides as Siglec-7 ligands

Cited by 10 publications

References 66 publications

Modulation of immune cell reactivity with cis -binding Siglec agonists

Modulation of immune cell reactivity with cis -binding Siglec agonists

CD22-Binding Synthetic Sialosides Regulate B Lymphocyte Proliferation Through CD22 Ligand-Dependent and Independent Pathways, and Enhance Antibody Production in Mice

Design, Synthesis, and Biological Evaluation of Small, High-Affinity Siglec-7 Ligands: Toward Novel Inhibitors of Cancer Immune Evasion

Contact Info

Product

Resources

About