The Peterson lab at KU focuses on the design, synthesis, and evaluation of biologically active small molecules. We are particularly interested in constructing molecular tools that can be used to manipulate biological processes. Our core science is organic chemistry, and we use modern methods of solution-phase and solid-phase synthesis to prepare modulators of biological pathways and probes of cellular biology. To investigate the activity and potency of these compounds, we employ diverse cellular and biochemical assays, with a particular emphasis on fluorescence-based techniques. Three of our research interests are outlined below.
We are studying compounds that mimic receptors found on the surface of living mammalian cells. These artificial cell surface receptors chemically modify cell surfaces and enable the delivery of cell-impermeable molecules through a mechanism similar to natural receptor-mediated endocytosis. We synthesize small artificial cell surface receptors by coupling ligand-binding motifs to the membrane anchor N-alkyl-3beta-cholesterylamine. When added to mammalian cells, this membrane anchor inserts into cellular plasma membranes, projects the ligand-binding motif from the cell surface, and rapidly cycles between the cell surface and intracellular early/recycling endosomes, engaging a membrane trafficking pathway accessed by many natural cell surface receptors. Cells treated with these synthetic receptors gain the ability to internalize specific drugs, proteins, and other poorly permeable molecules. This strategy, termed synthetic receptor targeting, can be used to define new pathways across biological membrane barriers both in vitro and in vivo. The construction of artificial cell surface receptors as molecular prostheses, designed to seamlessly augment the molecular machinery of living cells, represents an exciting new frontier in chemical biology.
We synthesize and evaluate small molecules designed to impact functions of cellular receptors and enzymes. In one research thrust, we are investigating small molecules that bind nuclear hormone receptors such as the estrogen and androgen receptors, proteins that control the proliferation of hormone-dependent breast and prostate cancers. These compounds have potential as novel anticancer agents, and, when linked to other protein-binding motifs, provide tools for the identification of targets of small molecules. Another area of interest involves the design of antiviral nucleosides such as 5-nitrocytidine, compounds designed to target viral RNA-dependent RNA polymerases.
Fluorescent small molecules represent powerful molecular probes that complement other biochemical and genetic approaches for dissecting biological systems. We synthesize novel fluorescent molecular probes to provide improved assays for characterizing the biological activity of synthetic compounds and as methods to label cellular targets and components. Some of our recent work in this area has included the synthesis of the cell-permeable Pennsylvania Green fluorophore and biologically active derivatives. This hybrid of Tokyo Green and Oregon Green is substantially more hydrophobic, photostable, and pH-insensitive than fluorescein, making it a potentially ideal probe of intracellular processes.
