We seek to establish a core facility for the synthesis of combinatorial chemical libraries and for the screening of HIV protease inhibitors. The core facility will be equipped with an Argonaut TridentTM automated synthesizer and a Zymark AllegroTM high throughput screening workstation. The Trident automated synthesizer is a flexible instrument that can be operated in semi- and fully-automated modes allowing the synthesis of small and large libraries in parallel as well as in the split-and-pool methods. This synthesizer is an ideal instrument to carry out multistep solution and solid-phase reactions involving difficult chemistry over a wide range of reaction conditions. The Allegro high throughput screening workstation is a modular system that allows optimization and flexibility of assay conditions necessary to perform a variety of assays. The instrument is capable of fast and accurate liquid handling as well as a variety of assay readout options and can carry out hundreds of screening experiments per day. The goal of the core facility is to generate chemical diversity using well established combinatorial chemical synthesis methods and screen inhibitors of wild-type and mutants HIV proteases. Both in parallel and the split-and-pool synthesis approaches will be used. Peptidomimetic and non-peptidomimetic scaffolds will be used to generate chemical libraries. Natural and unnatural residues will be synthesized and linked via a variety of backbone structures during combinatorial chemical library synthesis. The high throughput screening component of the core facility will allow the development of new screening methods and identification of new ligands that can target specific structures and sequences of wild-type and mutant HIV proteases. The primary connection between the core facility and the program project will be with the Schiffer, Gilson, and Tidor groups. The goals of their proposed research rely on the synthesis of combinatorial chemical libraries and identification of HIV protease ligands. In addition, the Swanstrom group will impact the core facility through providing us with the knowledge of resistance mechanisms and toxicity studies on new inhibitors. The results of combinatorial chemical synthesis and screening approaches will allow the generation of rapid feedback to test the theoretical design criteria developed using computational methods.
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