# Exploring Siglec-glycan ligand interactions using chemoenzymatic approaches

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2024 · $809,851

## Abstract

PROJECT SUMMARY/ABSTRACT
 Regulation of the immune system is substantially influenced by glycosylation. Cell-surface glycans tune
ligand-receptor binding and set a threshold for initiating the downstream signaling for immune cell activation.
Siglecs (sialic acid-binding immunoglobulin-type lectins) are a family of regulatory receptors involved in these
processes. A Siglec can bind to both cis and trans sialylated glycan ligands that are expressed on the same or
interacting cells, respectively. The binding of Siglecs with their ligands can either segregate Siglecs from
activation receptors or move them closer. The ability of inhibitory Siglecs to modulate activation receptors is
regulated by spatial proximity: recruiting Siglecs to the immune synapse in the proximity of activation receptors
would trigger inhibitory signaling to suppress immune-system activation, whereas moving Siglecs away from
activation receptors would enable optimal signaling through activation receptors.
 For the above reasons, recently, Siglecs have been described as glyco-immune checkpoints. Through
their interaction with sialylated glycans aberrantly expressed on tumor cells, innate immune cell-associated
Siglecs trigger signaling cascades to inhibit immune-system activation. Likewise, Siglecs upregulated on tumor
cells interact with yet-to-be identified T-cell membrane glycoproteins to suppress T cell anti-tumor functions.
On the positive side, however, inhibitory signaling through Siglecs curbs inflammation during cell death
induced by viral infection. Despite these intriguing observations, the mechanisms underlying the above
processes are just starting to be elucidated.
 The overarching goal of this project is to use a combination of chemoenzymatic, biochemical and
genetic tools to explore Siglec-glycan ligand interactions and their therapeutic implication. In Aim 1, we will
design Siglec-based chimeric switch receptors and convert inhibitory Siglecs into activation receptors. In Aim
2, we will use a cell-based glycan array platform to screen for high-affinity and specific ligands of Siglecs. Once
identified, we will explore their utilities to suppress or harness the inhibitory Siglec signaling for therapeutic
applications. Finally, we will use our chemoenzymatic tools to investigate how the Siglec-cis ligand interaction
is involved in mediating the Siglec–trans ligand interaction and accordingly immune cell activation (Aim 3).

## Key facts

- **NIH application ID:** 10845472
- **Project number:** 5R01AI154138-04
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Peng Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $809,851
- **Award type:** 5
- **Project period:** 2021-06-04 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10845472

## Citation

> US National Institutes of Health, RePORTER application 10845472, Exploring Siglec-glycan ligand interactions using chemoenzymatic approaches (5R01AI154138-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10845472. Licensed CC0.

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