Bioactive Signaling Molecules

Participants: Alexander, Chen, Cho, Comstock, Daniel, Dos Santos, Furdui, Howlett, Kim-Shapiro, King, Lowther, Lyles, Muday, Nelson, Newman, Parks, Poole, Salsbury, Welker

Questions: Researchers in this group synthesize or use naturally occurring molecules that modulate signaling pathways to understand the biological processes and to design new drugs.  Researchers use chemical biology (utilizing synthetic probes to discover modification sites in cells) and structural biology (analyzing protein conformation and dynamics) to detect “when and where” particular molecules bind to proteins and nucleic acids, and how the shapes and flexibility of proteins work together to send messages within the cell.  Areas of research focus include drug discovery including the design of novel technologies for treating, diagnosing, or studying the molecular and cellular mechanisms underlying human disease, the chemical biology of oxygen-, nitrogen- and phosphorus-linked modifications, structures and dynamics of metabolic, signaling and repair proteins, and the structure and function of disease-linked proteins emphasizing cancer, diabetes and arthritis.

Technology: Technology development is a key component of current research in this group; researchers in chemical biology design, synthesize, and test chemical probes that are used within cells to track protein oxidation sites and phosphorylation reactions. Researchers design compounds that can be used as anticancer drugs, redox regulators and proteomic labeling compounds, immunology and autoimmune disease modulators, nanomedicines and drug delivery, and study drug discovery platforms and methodology for chemical synthesis.

Analyses using these probes provide a wide range of information about protein chemistry, structure, and dynamics and require a research environment rich in high-end instrumentation, including imaging, high resolution mass spectrometry (MS), nuclear magnetic resonance spectroscopy, and X-ray crystallography.  Facilities exist at WFU to support these activities, particularly within the Center for Structural Biology and the Biology, Biochemistry and Chemistry departments.

Emphasis Group Activities: Members of this group participate in the Structural and Computational Biophysics monthly seminars and the Drug Discovery monthly working meetings. Activities of this subgroup are organized by Uli Bierbach.

Implications: The activity of proteins is highly regulated by endogenous small molecules that bind and change their conformation.  These binding events are central to signaling pathways and this group identifies both new molecules that can modulate proteins, as well as how these molecule affect protein structure and function. Isolation of endogenous small molecules and synthesis of new compounds that target these proteins to control their activity is an essential step in designing drugs and understanding how signaling pathways are regulated.