# Development of Cell-Permeable Peptides and Proteins

> **NIH NIH R35** · OHIO STATE UNIVERSITY · 2021 · $507,174

## Abstract

Research Summary
 Current FDA-approved drugs are usually either small molecules (MW <500) or large proteins (MW
>5000). Small molecules are generally limited to targeting proteins and other biomolecules that contain
deep binding pockets (e.g., enzymes and GPCRs), which represent ~10% of all disease relevant human
proteins. On the other hand, biologics (e.g., monoclonal antibodies) are restricted to extracellular targets,
which represent another ~10% of all drug targets. The remaining ~80% drug targets, which are primarily
proteins involved in intracellular protein-protein interactions (PPIs), are currently undruggable by either
approach. The same limitations apply to the use of small molecules and proteins as research tools. The
overall goal of my research is to develop a general approach to targeting the ~80% undruggable
proteins. Recent work from my lab as well as many other laboratories has demonstrated that mono- and
bicyclic peptides in the 700-2000 molecular-weight range act as effective PPI inhibitors. My group further
demonstrated that by integrating a newly discovered class of cyclic cell-penetrating peptides (CPPs) into
our compound design, we can generate cell-permeable and metabolically stable cyclic peptide inhibitors
against a wide variety of intracellular enzymes and PPIs. During the next five years, we plan to further
investigate the mechanism of action of these cyclic CPPs and use the knowledge to develop additional
CPPs of improved properties, e.g., CPPs with specificity for tumor tissues. The CPPs will be explored for
delivery of proteins as therapeutics and research tools. Efforts will also be made to optimize the potency,
selectivity, metabolic stability, and other drug properties of cyclic peptide inhibitors already discovered
against several important drug targets including calcineurin, CAL PDZ domain, and NEMO. Finally, we
plan to develop a novel methodology for synthesizing and screening large libraries of non-peptidyl
macrocycles that can passively diffuse into mammalian cells and act as inhibitors against intracellular
proteins such as PPIs.

## Key facts

- **NIH application ID:** 10151633
- **Project number:** 5R35GM122459-05
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Dehua Pei
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $507,174
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151633

## Citation

> US National Institutes of Health, RePORTER application 10151633, Development of Cell-Permeable Peptides and Proteins (5R35GM122459-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10151633. Licensed CC0.

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