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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.
Biochemistry/Chemical Biology/Medicinal Chemistry/Organic Synthesis
Our research focuses on protein-protein interactions in human cells and involves two types of studies at the interface of organic chemistry and molecular/cell biology. The first type (chemical biology) involves the development of chemical methods/tools and their application to discover new protein-protein interactions in biological processes (e.g., cell signaling). The second type (medicinal chemistry) involves the development of high-throughput methodologies to synthesize and screen macrocyclic compound libraries for protein-protein interaction inhibitors and novel therapeutic agents. The following projects are under current investigation in our group.
- Discovery of Ligands of Protein-Binding Domains. In eukaryotic cells, many protein-protein interactions are mediated by small protein-binding domains (e.g., SH2, PTB, BIR, BRCT, BUZ, and PDZ domains) which recognize short peptide motifs in their partner proteins. We employ a chemical/bioinformatics approach to identify the in vivo binding partners of these domains. First, a protein domain is screened against a peptide library to identify its peptide recognition motif(s). The peptide motif is next used to search the human proteome to identify its potential cellular targets. Finally, the putative interactions are validated in vivo by cell biology and/or proteomics methods.
- Identification of Kinase and Phosphatase Substrates. In addition to protein-protein interaction (physical event), cells use posttranslational modifications such as phosphorylation (chemical event) to mediate and regulate cellular processes. More than a third of human proteins are reversibly phosphorylated on >100,000 serine, threonine, and tyrosine residues by the opposing actions of ~500 protein kinases and >100 phosphatases. We use a chemical/bioinformatics approach to identify the protein substrates of kinases and phosphatases. A peptide library is screened against a kinase or phosphatase of interest to determine its substrate specificity profile. The consensus sequence(s) is then used to search the protein databases to identify its potential protein substrates, which are subsequently validated by cellular techniques.
- Macrocycles as Protein-Protein Interaction Inhibitors. Protein-protein interactions represent a very exciting but also extremely challenging class of drug targets, because their binding sites are usually flat surfaces to which conventional small molecules (molecular weight <500) do not bind with high affinity or specificity. We and others have found that macrocycles (molecular weight of 500-2000) are very effective inhibitors of protein-protein interactions. We have recently developed a methodology to chemically synthesize and screen large libraries of natural product-like cyclic and bicyclic peptides. We are now applying this method to develop macrocyclic inhibitors against a variety of protein-protein interactions involved in human diseases (e.g., cancer, diabetes, and rheumatoid arthritis).
- Cell-Penetrating Peptides for Drug Delivery. A major obstacle in drug discovery is the inability of a drug candidate to cross the cell membrane in order to reach an intracellular target. This is especially problematic for peptide-, protein-, and nucleic acid-based drugs (e.g., siRNA). We recently discovered a small cyclic peptide, cyclo(Phe-Nal-Arg-Arg-Arg-Arg-Gln), as an exceptionally active membrane transporter. We are currently studying its mechanism of cell entry, searching for transporters of still higher activity, and applying the transporters to deliver small molecules, peptides, proteins, and nucleic acids into human cells.
Major Techniques in Research:
- Solid-phase synthesis of peptide and non-peptidic libraries
- Solution-phase synthesis of library building blocks and other small molecules
- High-throughput library screening and peptide sequencing by mass spectrometry
- Molecular cloning, expression and purification of proteins
- Biophysical characterization of proteins (e.g., fluorescence polarization and surface plasmon resonance)
- Enzyme kinetics and inhibition
- Mammalian tissue culture, co-immunoprecipitation, and western blotting
- Confocal microscopy
Current Sources of Research Funding:
- National Institute of General Medical Sciences
- National Cancer Institute
- National Institute of Dental & Craniofacial Research
- OSU Drug Discovery Institute
Current Employment of Recent Graduates:
PhD Students: Assistant Professor of Pharmacy, Catholic University of Daegu, South Korea; Scientist, Food and Drug Administration; Scientist, Nestle Research Center, Switzerland; Scientist, Bayer HealthCare; Senior R&D Chemist, Albemarle; Research Chemist, RTI International.
Postdoctoral Associates: Professor of Chemistry, Tsinghua University, China; Professor of Pharmaceutical Chemistry, University of Bonn, Germany; Associate Professor of Chemistry, Wuhan University, China; Associate Professor of Chemistry, China Agricultural University; Chemical Abstracts; Scientist, AstaTech, Inc.
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. Luechapanichkul, R., Chen, X., Taha, H. A., Vyas, S., Guan, X., Freitas, M. A., Hadad, C. M., and Pei, D. (2013) Specificity profiling of dual specificity phosphatase vaccinia VH1-related (VHR) reveals two distinct substrate-binding modes, J. Biol. Chem. 288, 6498-6510.
3. Thakkar, A., Trinh, T. B., and Pei, D. (2013) Global analysis of peptide cyclization efficiency. ACS Comb. Sci. 15, 120-129.
4. Wu, X., Upadhyaya, P., Villalona-Calero, M. A., Briesewitz, R., and Pei, D. (2013) Inhibition of Ras-effector interactions by cyclic peptides. Med. Chem. Commun. 4, 378-382.
5. Zhao, B.; Tan, P. H.; Li, S. S. C.; Pei, D. (2013) Systematic characterization of the specificity of the SH2 domains of cytoplasmic tyrosine kinases. J. Proteomics 81, 56-69.
6. Xiao, Q., Luechapanichkul, R., Zhai, Y., and Pei, D. (2013) Specificity profiling of protein phosphatases toward phosphoseryl and phosphothreonyl peptides. J. Am. Chem. Soc. 135, 9760-9767.
7. 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.
8. Trinh, T. B., Xiao, Q., and Pei, D. (2013) Profiling the substrate specificity of protein kinases by on-bead screening of peptide libraries. Biochemistry 52, ASAP (DOI:10.1021/bi4008947).