# Development of Location-specific Sialidase Inhibitors

> **NIH NIH R15** · CLEVELAND STATE UNIVERSITY · 2021 · $445,500

## Abstract

Project Summary/Abstract
Sialidases (also called neuraminidases) are glycosidases responsible for the removal of sialic acid (Sia)
residues (desialylation) from glycan portions of glycocojugates. By desialylation, sialidases are able to
modulate the functionality and stability of the Sia-containing molecules and are involved in both
physiological and pathological pathways. Previous and our recent study indicate that lysosomal Neu1
sialidase could relocate to the cell surface of macrophages upon LPS stimulation, where it causes
desialylation of TLR4 receptor, leading to TLR4 activation and subsequent production of pro-inflammatory
cytokines. Dysregulation of TLR4 activation by LPS is responsible for chronic and acute inflammatory
disorders that often causes dangerous disease like sepsis that still lacks specific pharmacological
treatment. The first objective of this application is to quantitatively profile the location-specific expression
of Neu1 sialidase that is critical for TLR4 activation and its subsequent signal transduction. Sialidase
inhibitors are useful tools for studying sialidase function and related mechanisms of the biological
pathways. More importantly, effective sialidase inhibitors can be used as drugs to regulate the pathological
pathways caused by sialidase, such as dysregulated TLR4 activation. Our recent study indicates that
currently available pan sialidase inhibitor and microbial sialidase inhibitors could not inhibit mammalian
sialidase effectively. Several mammalian sialidase inhibitors have been reported. However, current
sialidase inhibitor design has usually focused on active-site binding, neglecting the subcellular localization
of the active enzyme, therefore, they are less effective in vivo or may be even toxic as they will affect other
sialidases inside of the cells. The second objective of this application is to develop location-specific inhibitor
for Neu1 sialidase and define the Neu1 sialidase’s involvement in LPS/TLR4 signaling pathway. The
objectives of this project will be accomplished by three specific aims: (1) Profile Neu1 sialidase expression
and cell surface relocation in macrophages upon LPS stimulation; (2) Develop lysosome-targeting Neu1
sialidase inhibitors for effective regulating desialylation in LPS/TLR4 signaling pathway; (3) Develop cell
surface-targeting Neu1 sialidase inhibitors for effective regulating desialylation in LPS/TLR4 signaling
pathway. This study is innovative because it uses a novel approach that overcomes the current limitations
in (a) profiling sialidase expression and relocation and (b) inhibiting sialidase at subcellular location. The
proposed project is significant because it will (i) uncover specific desialylation that is critical to the
LPS/TLR4 signal pathway and (ii) develop novel sialidase inhibitors for effective regulation of desialylation
in LPS/TLR4 signaling pathway. Finally, this proposal will enhance the infrastructure of research and
education at Cleveland State Un...

## Key facts

- **NIH application ID:** 10359898
- **Project number:** 1R15GM144881-01
- **Recipient organization:** CLEVELAND STATE UNIVERSITY
- **Principal Investigator:** XUE-LONG SUN
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $445,500
- **Award type:** 1
- **Project period:** 2021-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359898

## Citation

> US National Institutes of Health, RePORTER application 10359898, Development of Location-specific Sialidase Inhibitors (1R15GM144881-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10359898. Licensed CC0.

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