Department of Medicinal Chemistry
Blake R. Peterson
Organic Synthesis, Bioorganic / Medicinal Chemistry, and Chemical Biology
The Peterson lab at KU Med. Chem. focuses on the design, synthesis, and evaluation of biologically active small molecules. 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. Four of our research interests are outlined below.
1) Chemical biology of cellular receptors
We are studying compounds that mimic receptors found on the surface of living mammalian cells. These artificial cell surface receptors can enable the delivery of cell-impermeable molecules through a mechanism similar to natural receptor-mediated endocytosis. These compounds are synthesized by coupling ligand-binding motifs to membrane anchors such as N-alkyl-3beta-cholesterylamine. When added to mammalian cells, this mimic of cholesterol inserts into cellular plasma membranes, projects the linked 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. In this way, these synthetic receptors can enable cells to internalize specific drugs, proteins, and other poorly permeable molecules that interact with the ligand-binding motif. 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.
2) Modulators of receptors and enzymes
To create small molecules with potential anticancer or antiviral activity, we synthesize compounds designed to control cellular receptors and enzymes involved in pathogenesis. We study structure-activity relationships to optimize activity and potency and allow the preparation of derivatives useful for the identification of specific target proteins. We have investigated ligands of nuclear hormone receptors involved in the proliferation of hormone-dependent breast and prostate cancers, antiviral ribonucleosides that function as inhibitors and mutagenic substrates of viral RNA-dependent RNA polymerases, and derivatives of poorly understood immunomodulators as tools for identification of cellular targets. Representative examples of compounds previously under investigation are shown above.
3) Synthetic mimics of viral peptides
The use of endocytic uptake mechanisms to deliver poorly permeable molecules into mammalian cells is often plagued by entrapment and degradation of material in highly hydrolytic late endosomes and lysosomes. To prevent the exposure of cargo to these destructive membrane-sealed compartments, we are synthesizing compounds designed to mimic membrane escape mechanisms employed by viruses and other intracellular pathogens. By targeting pH-dependent membrane-lytic peptides such as PC4 and a disulfide-linked fluorophore to less hydrolytic early/recycling endosomes of mammalian cells, membranes of these endosomes can be selectively disrupted, resulting in cleavage of the disulfide and escape of the fluorophore into the cytosol and nucleus with low toxicity. The ability to deliver disulfide-linked cargo into and release this cargo from relatively non-hydrolytic early/recycling endosomes may be useful for the delivery of a variety of sensitive molecules into living mammalian cells.
4) Fluorescent molecular probes
Fluorescent small molecules represent powerful molecular tools that complement other biochemical and genetic approaches for dissecting biological systems. We synthesize novel fluorescent molecular probes to label cellular targets of biologically active compounds and create sensors of biochemical changes in physiology. Some of our work in this area has included the synthesis of the Pennsylvania Green fluorophore and derivatives. 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.