The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) is causally associated with the development of Kaposi's sarcoma (KS), some malignant lymphomas and multicentric Castleman's disease. KS remains the most common AIDS-related malignancy, and no curative approach exists. We have found that a protein encoded by KSHV, called vFLIP, is necessary for the survival of KSHV-infected lymphoma cells. There is also evidence that vFLIP is expressed in KS lesions, and can enhance the appearance of KS-like lesions in a mouse model. This indicates that vFLIP is a promising target for the treatment of the diseases caused by KSHV. vFLIP can activate the NF-KB and AP-1 signaling pathways, and is expressed during latent viral infection. Inhibition of vFLIP results in suppression of the constitutive NF-KB activity, downregulation of a specific set of antiapoptotic proteins and apoptosis of KSHV-infected cells. We have found that vFLIP directly interacts with TRAF2 through a specific TRAF-interacting motif, and that this interaction is essential for signaling by vFLIP. Therefore, our aim is to disrupt this interaction as a novel approach for the treatment of KSHV-associated diseases. Since protein-protein interactions have proven largely intractable to modulation using traditional """"""""drug-like"""""""" molecules, we propose to achieve this by synthesizing and screening libraries of natural product-like molecules. Specifically, we will use polyketide libraries since this class of compounds has a demonstrated ability to modulate protein-protein interactions through peptidomimicry and is structurally distinct from typical drug-like molecules. We will synthesize both a parent library and biased libraries that are specifically designed to target the vFLIP/TRAF2 interaction. Screening will be done using a cell-based luciferase reporter assay, as well as a recombinant protein homogeneous time-resolved fluorescence (HTRF) assay. Our long-term goal is to identify potential therapeutic lead compounds that will be tested in murine models of KSHV-associated diseases followed by further preclinical development and eventually clinical trials. ? ? ?