Current anti-HIV drugs target only a small subset of HIV-encoded proteins, such as reverse transcriptase and the viral protease. However, the HIV genome encodes fifteen proteins, and many of these are potential drug targets. Indeed, the function of many of these proteins is still unclear. The objective of the proposed research is to generate a panel of novel, useful, high-affinity small molecule ligands for HIV genome-encoded proteins. These molecules have the potential to modulate the function of the proteins to which they bind, thus helping to determine their biological function. Additionally, these molecules may be suitable for lead development as potential novel antivirals. Towards this end, we have developed a novel procedure for screening and identifying small molecule ligands for proteins. This procedure involves the synthesis of large, fluorescently-tagged, mixture-based combinatorial libraries, and screening of these libraries against dozens of protein targets simultaneously using protein microarrays. Binding of ligands is detected using ultrasensitive fluorescence microscopy, and the identity of the bound ligand is determined using a robot- assisted iterative deconvolution synthesis protocol. As part of our overall goal to develop and expand this technology to make proteome-wide antiviral discovery possible, the specific aims of this proposal are (1) To generate protein microarrays that comprise the proteins encoded by the HIV genome; and (2) To use our novel screening and ligand identification procedure to identify and characterize small molecule ligands that bind and regulate HIV-encoded proteins. These experiments will test the suitability of the ligand discovery technology for rapid library screening and ligand identification, and will result in a panel of small molecule modulators of HIV that will be useful in elucidating the function of HIV-encoded proteins and may serve as lead compounds for the treatment of HIV infections. ? ? ?
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