This proposal seeks to gain insight into interactions between protein beta-sheets, with the broad long-term objective of developing new compounds that can control this important, but underappreciated, class of protein-protein interactions. Interactions between protein beta-sheets occur widely and are represented significantly in about 15% of the protein structures in the Protein Data Bank (PDB). Protein beta-sheet interactions play a critical role in many biological processes associated with normal healthy function and in diseases ranging from cancer and AIDS to anthrax and Alzheimer's disease. ? ? The investigators will gain insight into interactions between protein beta-sheets by developing and studying chemical models of beta-sheets that bind proteins by means of beta-sheet interactions. These chemical models will be cyclic compounds containing a new amino acid building block that the investigators invented (Hao) and a new turn unit that the investigators discovered (delta-linked ornithine). The investigators will study the binding of cyclic chemical models of the CH1 domain of Fab to protein G domain III, to gain insight into interactions between protein beta-sheets and to determine what is necessary to create relatively simple chemical compounds that participate in the same types of beta-sheet interactions as much larger proteins. The investigators will use these systems and the insights gained from these studies to develop compounds that block the aggregation of beta-amyloid and Huntington, which are associated with Alzheimer's and Huntington's diseases. ? ? By developing synthetic compounds that bind to a real protein domain and bind proteins associated with important neurodegenerative diseases, these studies will further the long-term objective of creating compounds that can control interactions between protein beta-sheets. These insights and new compounds may eventually pave the way to new drugs to treat diseases and improve human health. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM049076-13
Application #
7324109
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Fabian, Miles
Project Start
1994-04-01
Project End
2010-11-30
Budget Start
2007-12-01
Budget End
2010-11-30
Support Year
13
Fiscal Year
2008
Total Cost
$252,598
Indirect Cost
Name
University of California Irvine
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Cheng, Pin-Nan; Liu, Cong; Zhao, Minglei et al. (2012) Amyloid ?-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity. Nat Chem 4:927-33
Cheng, Pin-Nan; Nowick, James S (2011) Giant macrolactams based on ýý-sheet peptides. J Org Chem 76:3166-73
Zheng, Jing; Liu, Cong; Sawaya, Michael R et al. (2011) Macrocyclic ýý-sheet peptides that inhibit the aggregation of a tau-protein-derived hexapeptide. J Am Chem Soc 133:3144-57
Liu, Cong; Sawaya, Michael R; Cheng, Pin-Nan et al. (2011) Characteristics of amyloid-related oligomers revealed by crystal structures of macrocyclic ?-sheet mimics. J Am Chem Soc 133:6736-44
Gothard, Chris M; Nowick, James S (2010) Nanometer-scale water-soluble macrocycles from nanometer-sized amino acids. J Org Chem 75:1822-30
Khakshoor, Omid; Lin, Aaron J; Korman, Tyler P et al. (2010) X-ray crystallographic structure of an artificial beta-sheet dimer. J Am Chem Soc 132:11622-8
Levin, Sergiy; Nowick, James S (2009) A new artificial beta-sheet that dimerizes through parallel beta-sheet interactions. Org Lett 11:1003-6
Khakshoor, Omid; Nowick, James S (2009) Use of disulfide ""staples"" to stabilize beta-sheet quaternary structure. Org Lett 11:3000-3
Khakshoor, Omid; Nowick, James S (2008) Artificial beta-sheets: chemical models of beta-sheets. Curr Opin Chem Biol 12:722-9
Khakshoor, Omid; Demeler, Borries; Nowick, James S (2007) Macrocyclic beta-sheet peptides that mimic protein quaternary structure through intermolecular beta-sheet interactions. J Am Chem Soc 129:5558-69

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