Christine S. Chow Title Professor Division Biochemistry Education A. B., Bowdoin College, 1987 M. A., Columbia University, 1988 Ph. D., Caltech, 1992 NIH Postdoctoral Fellow, M.I.T., 1992-94 Office Chem 441 Phone (313)577-2594 E-Mail Group http://chem.wayne.edu/chow

One of the long-term objectives of our research program is to understand the structural and functional roles of modified nucleosides in RNA. Although over 100 modifications and their locations in tRNAs and rRNA molecules have been identified, many questions still exist regarding the individual contributions of these modifications to RNA structure and function. Research in our group focuses on methodologies for the site-specific incorporation of modified nucleosides into RNA. The first approach involves the synthesis of natural nucleosides and their conversion into phosphoramidites with novel protective groups. The second approach involves a complementary enzymatic incorporation of the same modified bases that can be applied to larger, biologically interesting RNA molecules. The effects of modified bases on the structure and stability of ribonucleotide fragments (model RNAs) are being examined by a variety of biophysical methods. We are also using inorganic molecules to examine RNA structure. In particular, we employ rhodium(III) and ruthenium(II) complexes to probe the structural roles of modified bases and base mismatches in RNA model systems, as well as in large RNA systems.

Studies in our laboratory have also focused on the characterization of drug-RNA interactions in solution using fluorescence spectroscopy and other biophysical techniques, such as mass spectrometry. RNAs that can detect antibiotics, metal ions, and small organic molecules have been synthesized. Specifically, the RNAs have been converted into biosensors by labeling their 5' or 3' ends with fluorescent dyes such as fluorescein. These RNA sensors undergo fluorescence enhancement or quenching depending on the nature of the ligand interaction. A fluorescein-labeled A-site RNA analog is able to detect binding of aminoglycosides with a high level of specificity. This system provides a quantitative tool for the study of drug or metal-ion binding to RNAs in solution and also allows real-time monitoring of drug binding to RNA.

We are also involved with a collaborative program supported by the NIH that integrates a combinatorial genomic technology with structural biology and combinatorial chemistry with Profs. Philip Cunningham (Biological Sciences) and John SantaLucia (Chemistry). These experiments focus on the small ribosomal subunit. The long-term goal is to develop new anti-infectives that address the issue of antibiotic resistance. Interactions of drug leads with their rRNA targets are characterized using a variety of biophysical methods to identify compounds with the highest binding affinity and specificity.

Sumita, M.; Desaulniers, J.-P.; Chang, Y.-C.; Chui, H. M.-P.; Clos, L., II; Chow, C. S. "Effects of Nucleotide Substitution and Modification on the Stability and Structure of Helix 69 From 28S rRNA", RNA 2005, 11, 1420-1429.

Chow, C. S.; Cunningham, P. R.; Lee, K.-S.; Meroueh, M.; SantaLucia, J., Jr.; Varma, S. "Photoinduced Cleavage by a Rhodium Complex at G-U Mismatches and Exposed Guanines in Large and Small RNAs", Biochimie 2002, 84, 859-868.

Llano-Sotelo, B.; Azucena, E. F., Jr.; Kotra, L. P.; Mobashery, S.; Chow, C. S. "Aminoglycosides Modified by Resistance Enzymes Display Diminished Binding to the Bacterial Ribosomal Acyl-Transfer Site", Chemistry & Biology 2002, 9, 455-463.

Haddad, J.; Kotra, L. P.; Llano-Sotelo, B.; Kim, C.; Azucena, E. F., Jr. ; Liu, M.; Vakulenko, S. B.; Lee, H.; Chow, C. S.; Mobashery, S. "Design of Novel Antibiotics that Bind to the Ribosomal Acyltransfer Site", J. Am. Chem. Soc. 2002, 124, 3229-3237.

Chui, H. M.-P.; Desaulniers, J.-P.; Scaringe, S. A.; Chow, C. S. "Synthesis of Helix 69 of E. coli 23S rRNA Containing its Natural Modified Nucleosides, m3ψ and ψ ", J. Org. Chem. 2002, 67, 8847-8854.