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.
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| 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 |
| Woods, R Jeremy; Brower, Justin O; Castellanos, Elena et al. (2007) Cyclic modular beta-sheets. J Am Chem Soc 129:2548-58 |
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