Awards
NIH First Award, 1998
Camille Dreyfus Teacher Scholar Award, 2002

Research Interests 
Our research is in the area of bioorganic chemistry, where the principles of organic chemistry are applied to understanding biological phenomena. Using this interdisciplinary approach, we are defining the molecular basis for, and functional consequence of, protein-RNA and small molecule-RNA binding.

RNA-editing adenosine deaminases. One area under investigation is the study of the mechanism of RNA-editing adenosine deaminases. These enzymes have the ability to designate specific adenosines within an mRNA molecule for deamination. This reaction alters the information content in the mRNA, thus changing the structure of the encoded protein. One avenue we are pursuing to investigate this fascinating process is to synthesize modified nucleosides, which, when incorporated into model substrates, reveal details of the deamination reaction mechanism. These studies involve the development of synthesis strategies to protected ribonucleoside phosphoramidites, protein expression systems to provide the editing enzyme in sufficient quantity for study and enzyme assays to characterize the resultant RNA-protein complexes.

PKR, the RNA Dependent Protein Kinase. We are also studying a human protein kinase (PKR) that is regulated by binding RNA. This enzyme helps fight against viral infection by inhibiting viral protein synthesis in infected cells. Using a variety of chemical and biochemical techniques, we are defining how RNA binds PKR and how the protein kinase activity is controlled by the RNA-binding event (Figure 1).

Figure 1 A molecular model of the complex formed by the binding of the RNA-binding domain of PKR to TAR RNA from HIV-1.

RNA-specific ligands by combinatorial synthesis. Controlling the function of specific RNAs within a cell is possible by the use of low molecular weight, cell permeable compounds that bind specifically to the RNA. Unfortunately, the number of naturally occurring compounds with the required properties is rather limited. To increase the number of specific RNA binding molecules, and to define design features in a ligand necessary for RNA binding, we are synthesizing and screening combinatorial libraries for compounds that bind RNA.

The libraries are composed of peptides that have an intercalator (acridine or quinoline) embedded in the peptide backbone we call PICs (peptide-intercalator conjugates). In a typical screen for RNA-binding PICs, a fluorescently labeled RNA is bound to the library members covalently attached to solid phase synthesis beads. The structure of the PIC is then determined by tandem mass spectrometry.

Figure 2 An active compound attached to a solid phase synthesis bead is identified in a screen for ligands that bind a viral RNA labeled with the fluorophore Cy5.

Selected Publications

• "Substrate Analogues for an RNA-editing Adenosine Deaminase: Mechanistic Investigation and Inhibitor Design" Eduardo A. Véliz, LaHoma M. Easterwood and Peter A. Beal, J. Am. Chem. Soc., 2003 , 125, 36, 10867-10876.
• "Peptide Quinoline Conjugates: A new class of RNA binding molecules" Malathy Krishnamurthy, Barry D. Gooch and Peter A. Beal, Org. Lett. , 2004 , 6, 1, 63-66.
• "Site-specific Incorporation of N 2 -Benzylguanosine in Epstein-Barr Virus Encoded RNA 1 Controls the Binding Sites Occupied by PKR" Sujiet Puthenveetil, Eduardo A. Véliz and Peter A. Beal, ChemBioChem, 2004 , 5, 383-386.
• "Global and Specific Effects of Nucleic Acid-Binding Ligands on Protein Synthesis" Abba Malina, Shakila Khan, Coby B. Carlson, Yuri Svitkin, Isabelle Harvey, Nahum Sonenberg, Peter A. Beal , and Jerry Pelletier, FEBS Lett ., 2004 (in press).
• "The Binding Selectivity of ADAR2's dsRBMs Contributes to RNA-editing Site Selectivity" Olen M. Stephens and Peter A. Beal, Chem. Biol ., 2004 (in press).
• "Recognition of Duplex RNA by Helix-Threading Peptides" Barry D. Gooch and Peter A. Beal, J. Am. Chem. Soc. , 2004 (in press).
• "A Transition State Analog for an RNA-editing Reaction" Brittany L. Haudenschild, Olena Maydanovych, Eduardo A. Véliz, Mark R. Macbeth, Brenda L. Bass and Peter A. Beal, J. Am. Chem. Soc., 2004 (in press).