# Structural and Functional Synthetic Proteomimetics of Ankyrin Repeat Proteins

> **NIH NIH F32** · NORTHWESTERN UNIVERSITY · 2023 · $71,792

## Abstract

With the insight that tandem repeat proteins evolved from more homogeneous ancestors,1–3 our central
hypothesis is that their hallmark complex interaction surfaces can be emulated by simple synthetic
repeating constructs. We ask two key questions in the proposed research: 1) Can higher order folding of simple,
individual ankyrin repeats be induced by spatial organization on synthetic polymeric scaffolds allowing
multivalency, and thus replicating such interaction surfaces? and 2) What is the simplest ankyrin repeat that can
functionally recapitulate a high affinity PPI? To probe these questions, a polymer-based approach to
proteomimetics will be employed. The proposed proteomimetic systems will provide insight into ankyrin repeat
proteins by emulating the properties of proteins while remaining synthetically straightforward and structurally
simple.4 Specifically, we propose protein-like polymers (PLPs)5–10 as these constructs are monodisperse, protein-
sized macromolecules that are rapidly and scalably produced by polymerization of peptide-based monomers.
The result is a peptide brush polymer wherein peptides are tethered to a hydrocarbon polymer backbone in a
dense display. This results in a peptide topology that resembles repeat proteins, but where the peptides repeats
are arranged on a synthetic scaffold.6,7 We hypothesize that this proteomimetic platform can enable
conformational mimics of ankyrin repeat proteins, to serve as effective mimics for the disruption of PPIs as tools
and therapeutics. The long-term goal of this application is the precise design of tandem repeat-mimetic PLPs for
the formulation and delivery of therapeutic peptides and as chemical biology tools. With the combined knowledge
from these lines of inquiry, reliable rules will be established for the creation of highly stable, yet effective PLPs
that target protein-protein interactions in diseases. Furthermore, this knowledge will inform the design of
proteomimetic materials for therapeutic applications more broadly.
 In addition to this research project, a training plan will be pursued to develop the expertise and proficiency
of the candidate in soft matter synthesis and characterization, drawing upon the collaborative and motivated
research environment in Prof. Gianneschi's group and the considerable resources available through
Northwestern University. This plan will include honing skills in mentorship of students, presenting results,
effective grant-writing, and the management of research groups. This training plan and research environment
will help the candidate grow in their transition to new fields and lines of inquiry, towards the pursuit of an
independent research career investigating bio-inspired materials for targeted drug delivery.

## Key facts

- **NIH application ID:** 10694849
- **Project number:** 5F32GM143925-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Julia Oktawiec
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $71,792
- **Award type:** 5
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10694849

## Citation

> US National Institutes of Health, RePORTER application 10694849, Structural and Functional Synthetic Proteomimetics of Ankyrin Repeat Proteins (5F32GM143925-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10694849. Licensed CC0.

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