# Tailoring Structures of Sulfated Oligosaccharides for Modulating Heparanase Activity

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2022 · $328,210

## Abstract

PROJECT SUMMARY
 Heparanase is recognized as a master regulator of the aggressive phenotype of cancer,
an important contributor to the poor outcome of cancer patients and a prime target for therapy.
Although carbohydrate-based heparanase have been developed, but none were translated into
use in the clinic. Additionally, interaction of heparanase with heparan sulfate (HS) is regulated by
substrate sulfation sequences, and only substrates with specific sulfation patterns are cleaved
by heparanase. Although the crystal structure of human heparanase has been recently resolved,
it still does not allow determination of the structure of binding epitopes with defined N-and O-
sulfation patterns at each subsite of heparanase. To address these challenges, Aim 1 entails a
new modular chemical approach for the parallel combinatorial synthesis of a library of HS
trisaccharide substrates, representing all possible N-acetyl as well as O- and N-sulfation motifs.
Our strategy provides a systematic understanding of substrate specificity for heparanase and
how heparanase selects favorable cleavage site. In Aim 2, we propose to develop heparanase-
inhibiting sulfated oligosaccharides of high efficacy and clinical applicability. In Aim 3, the most
potent inhibitors developed in Aim 2 will be tested for cross-bioactivity to other HS-binding
proteins, which are responsible for mediating anticoagulant and angiogenic activity, antibody-
induced thrombocytopenia, and tumor cell metastasis. With the ultimate goal of understanding if
the in vitro inhibition of heparanase would translate in vivo, we will evaluate the effectiveness of
the most potent inhibitor(s) in inhibiting lymphoma tumor growth and experimental metastasis.
 Together, this project will provide insight into sulfate-recognition motifs and favorable
cleavage site for use to develop inhibitors of heparanase. The significant impact of this project is
that, if successful, it could lead to the discovery of a heparanase-inhibiting small carbohydrate
molecule for treatment of lymphomas, which are the fifth leading cancer in the North America,
produce tumors predominantly in lymphoid structures.

## Key facts

- **NIH application ID:** 10624518
- **Project number:** 3R01GM098285-09S1
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Hien M Nguyen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $328,210
- **Award type:** 3
- **Project period:** 2012-04-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10624518

## Citation

> US National Institutes of Health, RePORTER application 10624518, Tailoring Structures of Sulfated Oligosaccharides for Modulating Heparanase Activity (3R01GM098285-09S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10624518. Licensed CC0.

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