(AP5) AP5 supports the overall mission of this ICBG - discovering and developing therapeutic agents to treat invasive fungal infections and cancer - in several ways: dereplicating active compounds from bacterial extracts, discovering metabolites identified by genome mining, providing follow-up chemistry, housing the anticancer therapeutic discovery pipeline, administering overall group activities, and assisting in the development of both scientific personnel and research infrastructure in Brazil. These activities are embodied in four specific aims described below. 1. Identify and supply active molecules and derivatives to the antifungal and anticancer screening platforms. AP5 will speed up this traditional bottleneck by waiting for potency/selectivity data before beginning dereplicaton, using NMR techniques on partially purified fractions, and trying an new approach to high- throughput crystallography. 2. AP5 will also carry out studies to identify cryptic metabolites - molecules whose biosynthetic genes can be identified but that have never been characterized. AP5 will use two approaches: elicitor/co-culture stimulation and genetic knockouts coupled with differential metabolomics. 3. A high-throughput anticancer drug discovery pipeline that runs from primary assays to in vivo studies will be used to identify small molecules with therapeutic potential for blood cancers. These assays utilize 24 cell lines from 6 types of blood cancer, and all cell lines have been genomically characterized so that initial phenotypic screening results can reveal something about mechanism. 4. AP5 will also carry out many of the administrative functions: research agreements, database, communications, and training.
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