# Evolving New Glycosaminoglycan Mimetics

> **NIH NIH R01** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2021 · $384,183

## Abstract

Project Summary
Glycosaminoglycans (GAGs) play important roles in many physiological and pathological events
such as cell division, inflammation, neural development, and cancer metastasis. The long
polysaccharide chains of GAGs contain various sulfated disaccharides that are organized into
sulfate-rich and under-sulfated domains. This rich structural diversity enables GAGs such as
heparan sulfate (HS) to interact with numerous proteins and regulate key signaling pathways.
However, efforts to understand their structure-function relationships and harness their
therapeutic potential have been hampered by the chemical complexity of GAGs and a lack of
tools. At present, there are no tools to manipulate the interactions of GAGs with specific proteins
of interest, thus complicating efforts to pinpoint their precise roles. The goal of this project is to
develop novel chemical probes for selectively modulating GAG activity. We will use a directed
evolution-based approach to create a new class of GAG mimetics – multivalent glycopeptides
appended with short, active HS motifs – to modulate specific HS-protein interactions. Random
sampling of peptide sequences by directed evolution should allow for the selection of structures
containing the ideal number and arrangement of HS motifs. In addition to optimal HS clustering,
selected peptides should contain peptide motifs recognized by the protein of interest, thus
generating highly specific GAG probes. In Aim 1, we will work in collaboration with the Krauss
laboratory to develop the approach and generate HS mimetics that interact selectively with
fibroblast growth factor 2 (FGF2), a key growth factor involved in cell migration, angiogenesis,
and differentiation. In Aim 2, we will evolve glycopeptides that bind to specific forms of tau, a
microtubule-associated protein linked to dementias such as Alzheimer's disease and
Parkinson's disease. We will use these HS mimetics to understand the mechanisms underlying
tau uptake into neurons and neurodegeneration. In addition, we will explore whether our
mimetics can block the intercellular spreading of tau and its pathogenic consequences. In Aim 3,
we will evolve glycopeptides that bind chemokines (specifically CXCL9, CXCL10 and CXCL11),
a class of therapeutically important proteins that are key mediators of inflammation. Our probes
should provide unique insights into the paradoxical functional redundancy of chemokines,
enabling us to tease apart their individual roles. Together, these studies will produce a novel
class of GAG-based probes for understanding the physiological functions of GAGs and may
ultimately lead to new therapeutic leads or approaches to diseases such as cancer,
neurodegenerative diseases, inflammatory and autoimmune disorders, and infectious diseases.

## Key facts

- **NIH application ID:** 10217188
- **Project number:** 5R01GM127920-04
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Linda C Hsieh-Wilson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $384,183
- **Award type:** 5
- **Project period:** 2018-09-25 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217188

## Citation

> US National Institutes of Health, RePORTER application 10217188, Evolving New Glycosaminoglycan Mimetics (5R01GM127920-04). Retrieved via AI Analytics 2026-06-13 from https://api.ai-analytics.org/grant/nih/10217188. Licensed CC0.

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