Dehua Pei

Dehua Pei

Dehua Pei

Kimberly Professor

pei.3@osu.edu

614-688-4068

578 Biological Sciences Building
484 W 12th Ave
Columbus, OH 43210

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Areas of Expertise

  • Biochemistry
  • Organic

Bio

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 as an Assistant Professor of Chemistry. He was promoted to Associate Professor in 2001 and to Professor in 2004. 

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 ~80% 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) and the defective/missing proteins caused by genetic mutations. The goals of our research are 1) to understand how biomolecules enter the mammalian cell and 2) to develop a general strategy for drugging these challenging targets. The following projects are under current investigation in our group.

  • Macrocyclic Peptides as Protein-Protein Interaction Inhibitors. Protein-protein interactions (PPIs) represent an exciting but also very challenging class of drug targets, because they usually have large, flat binding sites, to which conventional 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 have developed a powerful technology to chemically synthesize and screen large libraries of cyclic and bicyclic peptides (up to 30 million different compounds) against essentially any protein of interest. We are currently applying this technology to discover macrocyclic peptide inhibitors against PPIs involved in human diseases (e.g., cancer, cystic fibrosis, inflammation, and autoimmunity). We are also developing new methodologies to synthesize and screen combinatorial libraries of non-peptidic, natural product-like macrocycles.

 

  • Mechanism and Application of Cell-Penetrating Biomolecules. The cell membrane represents a major obstacle in drug discovery, which is particularly problematic for peptide-, protein-, and nucleic acid-based drugs (e.g., siRNA). We have discovered a family of small cyclic peptides such as cyclo(phe-Nal-Arg-arg-Arg-arg-Gln) as powerful cell-penetrating peptides (CPPs), which are capable of efficiently delivering small molecules, peptides, proteins, and nucleic acids into the cytosol of mammalian cells. We discovered that CPPs enter cells by endocytic mechanisms and exit the endosome by a novel vesicle budding-and-collapse mechanism. We have also discovered non-peptidic cell-penetrating motifs (CPMs) that specifically deliver cargo molecules into the mitochondrial matrix. Current studies in this area include the discovery/design of additional CPPs/CPMs with improved properties (e.g., selectivity for cancer cells) and the cellular entry mechanisms of other synthetic drug delivery systems, bacterial toxins, and viruses.

 

  • Development of Intracellular Biologics and Chemical Probes. Biologic drugs (e.g., monoclonal antibodies) have transformed the drug industry over the past several decades but are so far limited to extracellular targets. We are leveraging the cyclic CPP technology to develop intracellular biologics as next-generation therapeutics and chemical probes. First, we are developing innovative strategies to use cyclic CPPs to deliver proteins, nucleic acids, and protein-nucleic acid complexes into the cell. Second, we are integrating the ligand discovery and cyclic CPP technologies from above to develop cell-permeable and metabolically stable macrocyclic peptide inhibitors against medicinally important but previously challenging PPI targets, such as calcineurin (inflammation), CAL PDZ domain (cystic fibrosis), MDM2 (cancer), NEMO (cancer and inflammation), and K-Ras (cancer). Finally, we have developed a general approach to engineering cell-permeable proteins by grafting short CPP motifs into their surface loops and are applying this strategy to design therapeutic proteins.

 


Selected Publications:

  1. Lian, W., Upadhyaya, P., Rhodes, C. A., Liu, Y., and Pei, D. (2013) Screening Bicyclic Peptide Libraries for Protein−Protein Interaction Inhibitors: Discovery of a Tumor Necrosis Factor-α Antagonist. J. Am. Chem. Soc. 135, 11990-11995.
  2. Qian, Z., Martyna, A., Hard, R. L., Wang, J., Appiah-Kubi, G., Coss, C., Phelps, M. A., Rossman, J. S., and Pei, D. (2016) Discovery and Mechanism of Highly Efficient Cyclic Cell-Penetrating Peptides. Biochemistry 55, 2601-2612.
  3. Qian, Z., Rhodes, C. A., McCroskey, L. C., Wen, J., Appiah-Kubi, G., Wang, D. J., Guttridge, D. C. and Pei, D. (2017) Enhancing the Cell Permeability and Metabolic Stability of Peptidyl Drugs by Reversible Bicyclization. Angew. Chem. Int. Ed. 56, 1525-1529.
  4. Rhodes, C. A., Dougherty, P. G., Cooper, J., Qian, Z., Lindert, S., Wang, Q.-E., and Pei, D. (2018) Cell-Permeable Bicyclic Peptidyl Inhibitors against NEMO-IkB Kinase Interaction Directly from a Combinatorial Library. J. Am. Chem. Soc. 140, 12102-12110.
  5. Appiah Kubi, G., Qian, Z., Amiar, S., Stahelin, R. V., and Pei, D. (2018) Non-peptidic Cell-penetrating Motifs for Mitochondrion-specific Cargo Delivery. Angew. Chem. Int. Ed. 57, 17183-17188.
  6. Dougherty, P. G., Sahni, A., and Pei, D. (2019) Understanding Cell Penetration of Cyclic Peptides. Chem. Rev. 119, 10241-10287.
  7. 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.
  8. 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.
  9. 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.
  10. Dougherty, P. G., Karpurapu, M., Koley, A., Lukowski, J. K., Qian, Z., Srinivas Nirujogi, T., Rusu, L., Chung, S., Hummon, A. B., Li, H. W., Christman, J. W., and Pei, D. (2020) A Peptidyl Inhibitor that Blocks Calcineurin-NFAT Interaction and Prevents Acute Lung Injury. J. Med. Chem., in press.

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