Harvesting microbial genomes for their therapeutic potential.
Nearly 50% of all anti-cancer agents and 75% of all known anti-microbial agents are natural products or have originated from natural products. Sequenced microbial genomes have provided an indication that we have only scratched the surface of the number of potential therapeutics produced by microbial systems. In this proposal, mass spectrometry based approaches will be developed to begin harvesting this untapped biotherapeutic goldmine. For new therapeutic discovery, emphasis is placed on orphan gene clusters that are likely to be responsible for the biosynthesis of protease inhibitors that target cathepsins, the proteasome, caspases and similar type of proteases. In addition, the targets of these newly discovered inhibitors will be established using DI-imaging-mass spectrometry and proteomic approaches. For the MALDI-imaging approach, specific cationic aldehyde inhibitors will be synthesized for the direct visualization of the target protease on histological reparations. For the proteomic approach, an irreversible inhibitor will be synthesized that would covalently link the protease to a resin at which point the identity is established using mass spectrometry. We anticipate that, if successful, both the cationic imaging approach and proteomic strategy will not only be useful to understand the binding location within tissues of the newly identified inhibitors but may also become a general strategy for identifying the targets of many other protease inhibitors.
Arnold O. Beckman exemplifies the meaning of the word humanitarian. Combined with his unwavering enthusiasm for life, his keen sense of humor and his strong moral and ethical principles, he is a national icon.