beta-Sheet interactions between proteins play a critical role in many biological processes associated with diseases and with normal function. Examples including the binding of Ras and Rap by the serine/threonine kinase Raf in cell signaling and oncogene expression, the dimerization of HIV protease, and the interaction between the CD4 receptor and the HIV viral protein gp120. beta-Sheet formation is also involved in the aggregation of peptides and proteins to form insoluble beta-sheet structures that are associated with a variety of devastating neurological disorders, including Alzheimer's disease, Creutzfeld-Jacob disease and other prion diseases, and Huntington's disease. This proposal seeks to mimic and to disrupt beta-sheet interactions by using chemical model systems called """"""""artificial beta-sheets."""""""" The broad, long-term objectives of this research encompass both the development of drugs for diseases involving beta-sheet formation between proteins (e.g., cancer, Huntington's disease, and Alzheimer's disease) and the development for general strategies for creating compounds that disrupt beta-sheet interactions.
The specific aims are as follows: (1) Artificial beta-sheet structures based upon the beta-sheet at the interface of the two halves of the met repressor dimer will be synthesized dimer will be synthesized, and their structures will be studied by NMR and CD spectroscopy. (2) An artificial beta-sheet designed to mimic the protein G binding region of the Fab portion of the immunoglobulin G will be synthesized, and its interaction with domain III of protein G will be studied by NMR spectroscopy. (3) An artificial beta sheet designed to mimic the beta-sheet interface between Ras proteins and the c-Rafl kinase (Raf) and artificial beta-sheets that mimic the binding regions of Ras and Raf will be synthesized. Their structures and interactions will be studied by CD and NMR spectroscopy, and the latter two compounds will be evaluated for anti-cancer activity by the NCI using an in vitro 60 human tumor cell line screen. (4) Artificial beta-sheets designed to mimic polyglutamine beta-sheet aggregates, which are involved in Huntington's disease and other genetic neurodegenerative diseases will be synthesized. Their structures will be studied by CD and NMR spectroscopy, and their ability to block polyglutamine beta-sheet aggregation will be determined using an in vitro assay. (5) Artificial beta-sheets designed to block beta-amyloid aggregation will be synthesized, and their abilities to block its aggregation and deposition will be studied using in vitro assays.
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