Organic / medicinal chemistry and chemical biology

The research group led by Prof. Blake R. Peterson at Ohio State creates chemical tools for the study of cancer biology and other biological systems. By conducting interdisciplinary research in the fields of bioorganic / medicinal chemistry and chemical biology, we investigate anticancer agents, molecular probes, methods for therapeutic targeting, and tools for target identification. Our expertise includes the synthesis of steroids, lipids, nucleosides, peptides, heterocycles, fluorophores, and protein conjugates, and the evaluation of these compounds in biochemical assays, whole cell assays, and model organisms. Our goal is to identify new therapeutic approaches and mechanisms. Two of our current research interests are described below.

Subcellular targeting for phenotypic drug discovery

Modern research in the pharmaceutical industry emphasizes cellular targeting as a strategy to improve the therapeutic index of anticancer agents. However, drug targets reside in specific subcellular locations, and the design of agents that might gain additional potency and selectivity by accumulating in specific subcellular compartments is relatively unexplored. We investigate small molecules that accumulate in specific organelles such as the endoplasmic reticulum to target receptors sequestered in these specific cellular compartments (Angew. Chem. Int. Ed. 2015, 54, 9696-9699) and develop sensitive sensors of biological processes such as activation of macrophages (ACS Chem. Biol. 2018, 13, 2595-2602). We are additionally investigating the combination of traditional cellular targeting agents with novel compounds that disrupt membranes of endosomes to create new types of synergistic anticancer agents (ACS Omega 2019, 7, 12955-12968). We are currently using subcellular-localized fluorescent probes in phenotypic high throughput and high content screening campaigns to identify small molecules with anticancer activity. Hits identified through this approach can be used to identify new protein targets for cancer drug discovery.

Synthetic molecular probes of biological systems

Fluorescent small molecules can often be used as sensitive molecular tools that complement biochemical and genetic approaches for dissecting biological mechanisms. We synthesize novel fluorescent molecular probes to explore mechanisms of action of biologically active compounds. Some of our work in this area has included the synthesis of the Pennsylvania Green fluorophore (Org. Lett. 2006, 8, 581-584) and biologically-active derivatives (Chem. Commun. 2015, 51, 14624-14627). This hybrid of Tokyo Green and Oregon Green is substantially more hydrophobic, photostable, and pH-insensitive than fluorescein, making it a valuable cell-permeable fluorophore. We recently developed a more efficient synthesis of the small coumarin Pacific Blue, a drug-like fluorophore that can facilitate studies of small molecule-protein interactions (ACS Omega 2016, 1, 1266-1276), and be readily analyzed in living cells by confocal microscopy and flow cytometry. We extensively use fluorescent imaging and analytical methods to investigate anticancer agents (ACS Chem. Biol., 2015, 10 (2), 570-576; Angew. Chem. Int. Ed. 2017, 36, 6927-6931) and explore associated biological processes.