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.
The Chemistry-Biology Interface Training Program (CBIP) at The Ohio State University
Biochemistry/Chemical Biology/Drug Discovery/Organic Chemistry
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 and the defective/missing proteins caused by genetic mutations. The goal of our group research is to find a general strategy for developing drugs against these challenging targets. Our research spans from fundamental mechanistic study of biological phenomena, development of novel methodologies, to applications of these mechanistic understanding and new methodologies to discover new chemical entities as therapeutic agents and chemical biology probes. The following projects are under current investigation in our group.
- Macrocycles as Protein-Protein Interaction Inhibitors. Protein-protein interactions 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 macrocycles in the molecular-weight range of 500-2000 serve as effective inhibitors of protein-protein interactions. We have developed a powerful technology to chemically synthesize and screen large libraries of cyclic and bicyclic peptides (up to 108 different compounds) against essentially any protein of interest. We are currently applying this technology to discover macrocyclic peptide inhibitors against protein-protein interactions involved in human diseases (e.g., cancer, cystic fibrosis, diabetes, and rheumatoid arthritis). We are also developing new methodologies to synthesize and screen combinatorial libraries of non-peptidic, natural product-like macrocycles.
- Cell-Penetrating Peptides for Drug Delivery. A major obstacle in drug discovery is that drug candidates often cannot cross the cell membrane to reach an intracellular target. This is particularly problematic for peptide-, protein-, and nucleic acid-based drugs (e.g., siRNA). We recently discovered that certain small, amphipathic cyclic peptides such as cyclo(Phe-Nal-Arg-Arg-Arg-Arg-Gln) are powerful membrane transporters, capable of very efficiently delivering small molecules, peptides, proteins, and nucleic acids into the cytosol of mammalian cells. We are currently investigating their mechanism of action and searching for additional transporters of still higher activity.
- Cell-Permeable Peptides and Proteins as Therapeutic Agents and Chemical Probes. The ligand discovery and delivery technologies from the above projects are being integrated to design small molecule-, peptide-, protein-, and nucleic acid-based therapeutics and chemical probes against medicinally important drug targets. Targets under current investigation include calcineurin (inflammatory diseases and organ transplantation), CAL PDZ domain (cystic fibrosis), MDM2 (cancer), NEMO (cancer and inflammation), Pin1 (cancer), PTP1B (type II diabetes), Ras (cancer), and TNF (autoimmunity and inflammation).
1. Qian, Z., Liu, T., Liu, Y.-Y., Briesewitz, R., Barrios, A. M., Jhiang, S. M., and Pei, D. (2013) Efficient delivery of cyclic peptides into mammalian cells with short sequence motifs. ACS Chem. Biol. 8, 423-431.
2. 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.
3. Qian, Z., LaRochelle, J. R., Jiang, B., Lian, W., Hard, R. L., Selner. N., Luechapanickhul, R., Barrios, A. M., and Pei, D. (2014) Early endosomal escape of a cyclic cell-penetrating peptide allows effective cytosolic cargo delivery. Biochemistry 53, 4034-4046.
4. Qian, Z., Dougherty, P., Liu, T., Oottikkal, S., Hogan, P., Hadad, C. M., and Pei, D. (2014) Structure-Based Optimization of a Peptidyl Inhibitor against Calcineurin-NFAT Interaction. J. Med. Chem. 57, 7792−7797.
5. Lian, W., Jiang, B., Qian, Z., and Pei, D. (2014) Cell-Permeable Bicyclic Peptide Inhibitors against Intracellular Proteins. J. Am. Chem. Soc. 136, 9830-9833.
6. Upadhyaya, P., Qian, Z., Selner, N. G., Clippinger, S. R., Wu, Z., Briesewitz, R., and Pei, D. (2015) Inhibition of Ras signaling by blocking Ras-effector interactions with cyclic peptides. Angew. Chem. Int. Ed. 54, 7602-7606.
7. Trinh, T. B., Upadhyaya, P., Qian, Z., and Pei, D. (2016) Discovery of a Direct Ras Inhibitor by Screening a Combinatorial Library of Cell-Permeable Bicyclic Peptides. ACS Comb Sci. 18, 75-85.
8. 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.
9. 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.
10. Bedewy, W., Liao, H., Abou-Taleb, N. A., Hammad, S. F., Nasr, T., and Pei, D. (2017) Generation of a Cell-Permeable Cycloheptapeptidyl Inhibitor against Peptidyl-Prolyl Isomerase Pin1. Org. Biomol. Chem.15, 4540-4543.