University of California, Santa Cruz, California, United States
Abstract: Natural products play a critical role as tools for advancing the fundamental understanding of human, plant and microbial biology and in the treatment of human disease. Natural product research programs have traditionally placed an emphasis on identifying novel chemical structures without fully exploring their biological activity. Typical natural product discovery groups utilize a small number of bioassays that only cover a small portion of biological processes. This time-intensive “grind and find” approach to natural product discovery has resulted in the frequent re-identification of known chemical scaffolds as well as an inability to identify molecules with unique bioactivity. These shortcomings highlight the fundamental gap between an understanding of the vast chemical complexity of small molecules and the biological functions they target.
Work in the MacMillan lab has focused on the development and use of broad-scale phenotypic screens to enhance the discovery and characterization of natural products from complex libraries. An example is FUnctional SIgnature of ONtology (FUSION), a “guilt by association” strategy that links bioactive natural products to the molecular entities or biological processes that they engage in cells. It employs an information-rich, high-throughput, endogenous reporter gene expression platform that allows quantitative discrimination of cellular responses to genetic and chemical perturbations. We have used this screen, in combination with untargeted metabolomics of the natural product fractions to enhance the discovery process. A second screen that will be discussed is the use of a molecularly annotated collection of non-small cell lung cancer cell lines that have been utilized for the discovery of selective cytotoxins that are coupled with a biomarker and a mechanism of action. Overall, these strategies will be aimed to show the enhanced value of complex phenotypic screening in natural product discovery.