# Rational design and functionalization of circular tandem repeat proteins

> **NIH NIH R01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2020 · $345,400

## Abstract

PROJECT SUMMARY/ABSTRACT
Natural evolution has produced a stunningly diverse array of proteins that perform an equally diverse set of
molecular functions in living organisms. These proteins—which constitute the primary raw material from which
we might seek to develop new protein reagents—have been honed over the course of their mutational history
to meet specific functional challenges. As a result, turning them to new functions by rational means often
proves problematic: their expression and/or stability are compromised by our reengineering attempts, and their
relic functionality is at odds with our intended use. De novo protein design, which uses sophisticated computer
algorithms to identify stable sequence:structure pairings without relying on native templates, can create protein
folds never before seen in Nature, and thus offers an alternative source of protein scaffolds for functionalization.
We recently reported the development of new algorithms for de novo design of a particular class of proteins—
circular tandem repeat proteins or cTRPs—whose modular, self-reinforcing symmetrical architecture offers
advantages that include high stability, tunable geometry, and switchable oligomeric state. We hypothesize that
de novo designed proteins in general, and these designed cTRPs in particular, will prove to be a valuable
source of protein scaffolds for downstream application. Our aims in this proposal are first, to further develop
our algorithms in order to design and experimentally validate a diverse set of cTRP scaffolds of varied size and
topology; and second, in collaboration with clinical colleagues here at the Hutchinson Center, to evaluate these
designs as scaffolds for presentation of functional domains with precisely controlled symmetry and geometry.
Our collaborators will test these designed constructs in cellular assays with the goal of speeding the
development of cellular therapies. Successful completion of this research will lead to (1) improved protein
design algorithms that have been rigorously validated across a range of topologies and are available to the
research community; (2) a family of stable and robust protein scaffolds for downstream functionalization, all of
whose members have been structurally and biophysically characterized; (3) a set of useful protein reagents for
biomedical applications.

## Key facts

- **NIH application ID:** 9897572
- **Project number:** 5R01GM123378-04
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Philip Bradley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $345,400
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9897572

## Citation

> US National Institutes of Health, RePORTER application 9897572, Rational design and functionalization of circular tandem repeat proteins (5R01GM123378-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9897572. Licensed CC0.

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