# Glycosylation as a Structural Determinant in Peptide Fibrillization

> **NIH NIH R35** · UNIVERSITY OF FLORIDA · 2021 · $375,596

## Abstract

Project Summary. All human cell surfaces and nearly half of all human proteins are decorated with
carbohydrates (i.e., glycosylated), yet our understanding of the role of glycosylation in health and disease
remains limited. Increasing evidence is establishing a central role for glycosylation as a determinant of protein
folding, sorting, processing, export, and function. Advancing this understanding requires platforms to
systematically study changes in protein form and function resulting from altered glycosylation, which has
historically required highly specialized expertise in protein production and carbohydrate synthesis. As a practical
alternative, my research program develops carbohydrate-modified peptides that self-assemble into fibrillar
architectures as synthetic analogs of glycosylated proteins. The proposed research program will study how
glycosylation influences peptide fibrillization as a surrogate for protein folding, and will use these insights to
enable design of new biomaterials. Preliminary data supporting the proposed research demonstrate that
glycosylation can facilitate hierarchical self-assembly of a synthetic b-sheet fibrillizing peptide into anisotropic
networks of aligned nanofibers. These anisotropic networks resist non-specific biological interactions yet
selectively recognize carbohydrate-binding proteins due to the emergent function of carbohydrates assembled
into a multivalent architecture. The overarching hypothesis of the proposed research is that glycosylation
influences peptide fibrillization and nanofiber function by establishing intermolecular forces that mediate specific
binding interactions while preventing non-specific associations. To test this, we will first develop a method for
scalable, cost-effective synthesis of a library of fibrillizing peptides modified with a broad range of carbohydrate
chemistries. Then we will use this library to study the influence of glycosylation on the kinetics of peptide
fibrillization and equilibrium morphology of the resultant nanofibers using various biophysical methods. Together,
these studies will establish fundamental understanding of glycosylation as a structural determinant in peptide
fibrillization. Finally, we will evaluate glycosylated peptide nanofibers as biomaterials that recapitulate the form
and function of lubricin, a cartilage glycoprotein that provides boundary lubrication at the joint surface, which is
lost during osteoarthritis progression. Although we use synthetic fibrillizing peptides as a model system, general
observations made through this research program are expected to be applicable to the biophysics of natural
fibrillizing peptides, and may also inform understanding of mucins and other densely glycosylated proteins.
Success of this research will advance the field of supramolecular biomaterials by establishing carbohydrates as
a new class of molecular motif for controlling peptide fibrillization. Ultimately, this research will support future
efforts ...

## Key facts

- **NIH application ID:** 10200093
- **Project number:** 5R35GM133697-03
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Gregory Hudalla
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $375,596
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200093

## Citation

> US National Institutes of Health, RePORTER application 10200093, Glycosylation as a Structural Determinant in Peptide Fibrillization (5R35GM133697-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10200093. Licensed CC0.

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