Biography

Dehua Pei obtained his B.S. Degree in Chemistry from Wuhan University, China in 1986 and his Ph.D. Degree in organic chemistry from University of California, Berkeley in 1991, working under the direction of Peter G. Schultz. After a postdoctoral stint with Christopher T. Walsh at Harvard Medical School, he joined the faculty at OSU in 1995. He was honored as OSU’s 2017 Innovator of the Year and named a fellow of American Association for the Advancement of Science in 2010. He received American Chemical Society Akron Section Award in 2009 and American Chemical Society Columbus Section Award in 2018. He co-founded Entrada Therapeutics in 2016 and served as its Chief Scientific Advisor in 2016-2021.

Research Overview

Biochemistry/Chemical Biology/Drug Discovery/Organic Chemistry

Our research spans from mechanistic study of biological phenomena, development of novel methodologies, to applications of the mechanistic understanding and methodologies to discover novel therapeutic agents and chemical probes. It is estimated that ~75% of all disease relevant human proteins are undruggable by current drug modalities, which include small molecules (molecular weight <500) and biologics (molecular weight >5000). Prominent examples of undruggable proteins are those involved in intracellular protein-protein interactions (PPIs). The ultimate goals of our research are to understand how biomolecules travel across cell membranes and develop a new class of drugs – intracellular biologics – to target these challenging proteins. The following projects are under current investigation in our group.

• How Do Biomolecules Cross the Cell Membrane? Most biomolecules (e.g., peptides, proteins, and nucleic acids) cannot travel across the cell membrane. Consequently, the cell membrane poses one of the biggest challenges in drug discovery. Nevertheless, viruses and an increasing number of folded proteins (e.g., bacterial toxins and certain eukaryotic proteins) are known to cross the cell membrane in both directions, but their mechanisms of action have been a longstanding mystery. We recently discovered a novel membrane translocation mechanism, vesicle budding and collapse (VBC), which drives the cellular entry of cell-penetrating peptides. We are currently investigating the potential involvement of VBC during the cellular entry of bacterial toxins and nonenveloped viruses as well as the unconventional secretion of folded proteins by eukaryotes. We are also leveraging our mechanistic understanding to design additional cell-penetrating peptides/proteins as more efficient drug delivery vehicles.
   
• Macrocyclic Peptides as Protein-Protein Interaction Inhibitors. PPIs represent an exciting but also challenging class of drug targets, because they usually have large, flat binding sites, to which small molecules do not bind with high affinity or specificity. We and others have demonstrated that macrocyclic peptides in the molecular-weight range of 500-2000 serve as effective PPI inhibitors. We also developed a powerful method to chemically synthesize and rapidly screen large libraries of macrocyclic peptides (up to 30 million different compounds) against essentially any protein of interest. We are currently applying this technology and medicinal chemistry strategies to discover macrocyclic peptide inhibitors against PPIs that cause human diseases (e.g., cancer, inflammation, and autoimmunity).
   
• Development of Intracellular Biologics and Chemical Probes. Biologic drugs (e.g., monoclonal antibodies) have transformed the drug industry over the last few decades but are limited to extracellular targets. We are now integrating the drug discovery and delivery technologies described above to develop intracellular biologics as next-generation therapeutics. Our first approach involves the conjugation of cyclic cell-penetrating peptides to peptides, proteins, and nucleic acids to render the latter cell permeable and biologically active. In our second approach, cell-penetrating and target-binding peptide moieties are integrated into the same molecular structures (or hybrids) that are capable of efficiently entering the cell and engaging PPI targets. Finally, we have engineered a family of membrane translocation protein domains (MTDs) and are using them to deliver potentially any protein into mammalian and plant cells.
   

Recent PhD Graduates

2019 Kuangyu Chen; Current Position: Clinical Scientist, Proctor & Gamble, Beijing, China

2019 Patrick G. Dougherty; Current Position: Scientist, Entrada Therapeutics, Boston, MA

2019 Curran A. Rhodes; Current Position: Postdoctoral Researcher, National Cancer Institute

2020 George Appiah Kubi; Current Position: Scientist, Entrada Therapeutics, Boston, MA

2021 Marina Buyanova; Current Position: Principal Scientist, Grove Biopharma, Inc. Chicago, IL

2021 Heba Salim; Current Position: Postdoctoral Scientist, Eli Lilly, Indianapolis, IN

2022 Amritendu Koley; Current Position: Scientist, Mytide Therapeutics, Boston, MA

2022 Ashweta Sahni; Current Position: Scientist, Entrada Therapeutics, Boston, MA

2022 Jordan Hempfling; Current Position: Scientist I, Curie Therapeutics, Woburn, MA

 

Selected Publications:

1. Dougherty, P. G., Wen, J., Pan, X., Koley, A., Ren, J.-G., Sahni, A., Basu, R., Salim, H., Appiah Kubi, G., Qian, Z., and Pei, D. (2019) Enhancing the Cell-Permeability of Stapled Peptides with a Cyclic Cell-Penetrating Peptide. J. Med. Chem. 62, 10098-10107.

2. Salim, H., Song, J., Sahni, A., and Pei, D. (2020) Development of a Cell-Permeable Cyclic Peptidyl Inhibitor against the Keap1-Nrf2 Interaction. J. Org. Chem. 85, 1416–1424.

3. Sahni, A., Qian, Z., and Pei, D. (2020) Cell-Penetrating Peptides Escape the Endosome by Inducing Vesicle Budding and Collapse. ACS Chem. Biol. 15, 2485-2492.

4. Chen, K., and Pei, D. (2020) Engineering Cell-Permeable Proteins through Insertion of Cell-Penetrating Motifs into Surface Loops. ACS Chem. Biol. 15, 2568-2576.

5. Dougherty, P. G., Wellmerling, J. H., Koley, A., Lukowski, J. K., Hummon, A. B., Cormet-Boyaka, E., and Pei, D. (2020) Cyclic Peptidyl Inhibitors against CAL-CFTR Interaction for Treatment of Cystic Fibrosis. J. Med. Chem. 63, 15773–15784.

6. Buyanova, M., Cai, S., Cooper, J., Rhodes, C., Salim, H., Sahni, A., Upadhyaya, P., Yang, R., Sarkar, A., Li, N., Wang, Q. E., & Pei, D. (2021) Discovery of a Bicyclic Peptidyl Pan-Ras Inhibitor. J. Med. Chem. 64, 13038–13053.

7. Sahni, A., and Pei, D. (2021) Bacterial Toxins Escape the Endosome by Inducing Vesicle Budding and Collapse. ACS Chem. Biol. 16, 2415–2422.

8. Buyanova, M., and Pei, D. (2022) Targeting Intracellular Protein-Protein Interactions with Macrocyclic Peptides. Trends Pharmacol. Sci. 43, 234–248.

9. Pei, D. (2022) How Do Biomolecules Cross the Cell Membrane? Acc. Chem. Res. 55, 309–318.

10. Buyanova, M., Sahni, A., Yang, R., Sarkar, A., Salim, H., and Pei, D. (2022) Discovery of a Cyclic Cell-Penetrating Peptide with Improved Endosomal Escape and Cytosolic Delivery Efficiency. Mol. Pharmaceutics 19, 1378–1388.