# Development of cell-permeable peptides and proteins

> **NIH NIH R35** · OHIO STATE UNIVERSITY · 2022 · $513,765

## Abstract

Project 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. In
addition, there are ~7000 human genetic diseases affecting ~10% of the US population; only a very
small fraction of them currently has pharmacologic treatment. The overall goal of my research is to
develop a general approach to targeting the ~80% undruggable proteins and treating human genetic
diseases. Accomplishing this goal requires effective delivery of large biomolecules into the mammalian
cell. Over the past decade, my group has discovered a novel class of cyclic cell-penetrating peptides
(CPPs), which efficiently deliver all major drug modalities into the cytosol of mammalian cells in vitro and
in vivo, and elucidated their mechanism of endocytic uptake and endosomal escape. During the next five
years, we will continue three areas of investigation. First, we will investigate how linear and cyclic CPPs
directly translocate across the plasma membrane, how bacterial toxins and some human proteins escape
the endosome into the cytosol, and how CPPs and some proteins exit the mammalian cell by a yet poorly
defined “unconventional protein secretion” mechanism. Second, we will use the mechanistic knowledge
gained to develop CPPs of improved properties, e.g., CPPs with specificity for tumor tissues, and
engineer a mammalian membrane translocation domain (MTD) for intracellular delivery of proteins.
Finally, we will leverage the cyclic CPPs and MTDs to develop cell-permeable peptides and proteins as
chemical probes and potential therapeutics against several key “undruggable” targets.

## Key facts

- **NIH application ID:** 10405784
- **Project number:** 2R35GM122459-06
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Dehua Pei
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $513,765
- **Award type:** 2
- **Project period:** 2017-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405784

## Citation

> US National Institutes of Health, RePORTER application 10405784, Development of cell-permeable peptides and proteins (2R35GM122459-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10405784. Licensed CC0.

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