# Targeted degradation of proteins by affinity peptide conjugated ubiquitin (APCU)

> **NIH NIH R21** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2021 · $200,318

## Abstract

Targeted degradation of proteins by affinity peptide conjugated ubiquitin (APCU)
Protein degradation possesses many unique properties that cannot be covered by DNA/RNA manipulation
tools. To understand the mechanism of biological processes, and to achieve desirable therapeutic effects,
techniques designed to induce protein degradation are in critical needs. However, very few options are
currently available for such purposes. Also, the existing tools have known limitations such as difficulty for
adaptation or bell-shaped dose-response curve, or vulnerability for a negative regulation by the de-
ubiquitination system. To expand the option for tools, and to overcome limitations of current methods, we
propose to establish a new approach to induce protein degradation by conjugating a ubiquitin moiety with a
molecule of high affinity to a target protein. For a proof or concept, peptides will first be used as the affinity
molecule. This prototype is thus called affinity peptide conjugated ubiquitin (APCU). In our preliminary study,
we designed a prototype APCU molecule with a peptide targeting MCL1, an oncoprotein that is over-expressed
in many types of cancer. We found that this molecule can specifically reduce the level of MCL1 protein by
promoting its degradation. In the proposed study, we will determine the action mechanism of the APCU
approach and the optimal conditions for designing this types of molecules. We will also determine the dose
response curve of the MCL1-targeting APCU and its sensitivity of de-ubiquitination system. Furthermore, to
prepare for a wide usage and future in vivo applications, we will test the application of APCU on several other
proteins and explore the feasibility of forming an APCU molecule with a conditional conjugation strategy. This
proposed study, if secedes, will provide a highly valuable tool to specifically degrade a protein for mechanistic
investigations and for potential therapeutic usages.

## Key facts

- **NIH application ID:** 10172275
- **Project number:** 1R21CA250597-01A1
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** FANGLIANG ZHANG
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $200,318
- **Award type:** 1
- **Project period:** 2021-04-12 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10172275

## Citation

> US National Institutes of Health, RePORTER application 10172275, Targeted degradation of proteins by affinity peptide conjugated ubiquitin (APCU) (1R21CA250597-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10172275. Licensed CC0.

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