Automated Synthesizer for Diversity-Oriented Synthesis of Peptides and Peptoids

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This application proposes to fund a cutting-edge system for automated synthesis of complex bio-active molecules. Peptides and related synthetic analogs are classes of linear molecules built up from various building blocks that are attached together in sequential connective steps. By varying which building blocks are in which position in the sequence, a staggering diversity of different molecules with different properties can be created. These steps are repetitive, iterative, and normally incredibly time consuming. It would take a full day to make one such molecule by conventional manual synthesis methods. The chemistry has been perfected to the point that they can done by automated systems. The requested automated parallel synthesizer can use more than 25 distinct building blocks and reagents, with heating, agitation, filtrations, and liquids handling all done robotically. The dozens of steps that are needed to make each molecule can be done without human intervention, and the computer-controlled system can make six such molecules at the same time in separate reaction vessels.******The Hof group propose innovative uses for these peptides and artificial peptide-like molecules. The many different peptidic compounds that are made in parallel will be incorporated into hybrid structures that also include binding element (a core binding pocket) and that sometimes include a sensing element (molecules that change color upon binding). We aim to make potent and selective molecular affinity reagents that will target and bind to other molecules. Future applications for these many novel binding reagents include the creation of new protein- and metabolite-binding research tools, the direct optical detection of illicit drugs in biofluid samples, the reversal of drug toxicity, and the creation of new kinds of diagnostics. ******The Hof group's research program was reliant on an older-generation peptide synthesizer, which catastrophically failed in November 2018. The new system that is requested offers both a replacement of this critical infrastructure, and also a key upgrade in that it has the cutting-edge ability to make 6 compounds at the same time in a fully automated process. This ability to make compounds in parallel is critical for the Hof group's new directions in diversity-driven chemistry.**