EXCEED THE SPACE PROVIDED, Reversible phosphorylation of proteins controls the execution and regulation of many cellular processes. A proper level of phosphorylation is critical for these processes and is controlled by the opposing actions of protein kinases and protein phosphatases. Imbalance of the two activities is known to cause many human diseases and conditions such as cancer, immunodeficiency, autoimmunity, diabetes, and obesity. The project has three long-term objectives: (1) to determine the sequence specificity of SH2 domains and protein tyrosine phosphatases (PTPs), (2) to identify the in vivo targets of SH2 domains and PTPs, and (3) to develop specific SH2 and PTP inhibitors as in vivo research tools and potential therapeutic agents. This project will focus on a subfamily of SH2 domain-containing PTPs, SHP-1 and SHP-2, as well as the prototypical phosphatase PTP1B. It consists of four specific aims.
Specific Aim 1 is to determine the binding specificity of five SH2 domains in SHP-1, SHP-2, and SHIP (an inositol phosphatase) using a combinatorial library approach.
Specific Aim 2 is to determine the primary sequence specificity of the catalytic domains in SHP-1, SHP-2, and PTPIB using combinatorial library methods.
Specific Aim 3 is to develop isoform-specific PTP inhibitors against PTPIB, SHP-1, and SHP-2 through a combination of rational design and the construction and screening of combinatorial inhibitor libraries.
Specific Aim 4 is to develop membrane permeable SH2 domain antagonists using a novel neutral phosphotyrosine mimetic. Inhibitors specific for PTP1B will provide potential treatment of type II diabetes and obesity, whereas inhibitors against Src SH2 domain is useful for treatment of cancer and osteoporosis. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062820-03
Application #
6834620
Study Section
Biochemistry Study Section (BIO)
Program Officer
Lograsso, Philip
Project Start
2003-01-01
Project End
2006-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
3
Fiscal Year
2005
Total Cost
$258,125
Indirect Cost
Name
Ohio State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Rhodes, Curran A; Pei, Dehua (2017) Bicyclic Peptides as Next-Generation Therapeutics. Chemistry 23:12690-12703
Qian, Ziqing; Dougherty, Patrick G; Pei, Dehua (2017) Targeting intracellular protein-protein interactions with cell-permeable cyclic peptides. Curr Opin Chem Biol 38:80-86
Dougherty, Patrick G; Qian, Ziqing; Pei, Dehua (2017) Macrocycles as protein-protein interaction inhibitors. Biochem J 474:1109-1125
Upadhyaya, Punit; Bedewy, Walaa; Pei, Dehua (2016) Direct Inhibitors of Ras-Effector Protein Interactions. Mini Rev Med Chem 16:376-82
Trinh, Thi B; Upadhyaya, Punit; Qian, Ziqing et al. (2016) Discovery of a Direct Ras Inhibitor by Screening a Combinatorial Library of Cell-Permeable Bicyclic Peptides. ACS Comb Sci 18:75-85
Trinh, Thi B; Pei, Dehua (2016) Screening One-Bead-One-Compound Peptide Libraries for Optimal Kinase Substrates. Methods Mol Biol 1360:169-81
Cheng, Ying; Chikwava, Kudakwashe; Wu, Chao et al. (2016) LNK/SH2B3 regulates IL-7 receptor signaling in normal and malignant B-progenitors. J Clin Invest 126:1267-81
Jiang, Bisheng; Pei, Dehua (2015) A Selective, Cell-Permeable Nonphosphorylated Bicyclic Peptidyl Inhibitor against Peptidyl-Prolyl Isomerase Pin1. J Med Chem 58:6306-12
Qian, Ziqing; Upadhyaya, Punit; Pei, Dehua (2015) Synthesis and screening of one-bead-one-compound cyclic peptide libraries. Methods Mol Biol 1248:39-53
Qian, Ziqing; Dougherty, Patrick G; Pei, Dehua (2015) Monitoring the cytosolic entry of cell-penetrating peptides using a pH-sensitive fluorophore. Chem Commun (Camb) 51:2162-5

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