Design of Membrane-Associated Signaling Modulators

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DESCRIPTION (provided by applicant): Ras proteins are membrane-associated proteins that modulate cell activation by acting as a molecular "on-off" switch of many receptor-coupled signaling pathways. Mutations of Ras protein leading to an activated state are found in about 25 % of oncogenic transformation. Certain Ras proteins also interacts with caveolin-1, a cholesterol-binding membrane protein that regulates cellular trafficking through a specific lipid microdomain (lipid raft) linked to receptorcoupled signal cascades. Both types of proteins contain lipids and membrane-binding domains for their membrane-associated functions. This application will focus on the development of Ras protein mimetics that are capable of membrane-tanslocation and membrane-association to modulate Ras signaling pathways. The key design of the Ras mimetics is a novel membrane permeable alpha/epsilon-peptide dendron with or without fatty acylated chains that function as transportants. Our immediate goals include the development of a novel synthetic platform based on tandem ligation for preparing reagents consisting of detection probes, membranepermeable dendrons, peptide cargoes or lipids to facilitate assays and mechanistic study in our experiments. The development of an effective strategy for targeting regulated intracellular delivery of macromolecules represents a long-term objective of our application. To achieve our goals, this application will use both chemical and biological tools. Specific Aim #1 will develop reagents and a synthetic platform for preparing Ras protein mimetics. Aims #2 and #3 will evaluate soluble membrane-permeable and membrane-associated Ras mimetics to inhibit Ras effectors and their association in lipid rafts. Aim #4 will compare the delivery mechanisms of Ras mimetics through endosomal pathway.