Carston R. Wagner

Professor and Director of Graduate Studies

Department of Medicinal Chemistry, Medical School

Email: wagne003@umn.edu
Phone: (612) 625-2614

Education

Ph.D., Duke University, 1987
NIH Postdoctoral Fellow, Chemistry, Pennsylvania State, 1987-1991

Research Interests

The multidisciplinary research program pursued by the students in my laboratory applies the areas of synthetic chemistry, medicinal chemistry, protein chemistry, enzymology, molecular biology, biochemical pharmacology, x-ray crystallography, spectroscopy and molecular modeling to the following research project areas.

1)Design and Development of Therapeutic Nucleotide Analogs.Our laboratory has begun a detailed analysis of the feasibility of using hydrophobic amino acid phorphoramidate prodrugs of antiviral and antitumor for the delivery of antiviral and anticancer nucleotides. A general synthetic methodology for prodrug construction has been achieved and biological testing is underway. Several of the compounds have demonstrated substantial antiviral and antitumor activity, both in vitro and in vivo. Preliminary mechanistic studies have revealed novel metabolic pathways for these compounds that may be responsible for their biological activity. In addition, based on these studies, a novel approach toward the generation of "nucleotidomimetic" antagonists of CAP dependent RNA translation is being explored.

2) Design and Study of Chemical Inducers of Protein Oligomerization. Protein oligomerization and dimerization initiated by small molecules and peptides play an important role in regulating signal transduction, gene expression, and metabolic processes. Nevertheless, the underlying molecular rules govening these processes are not well understood. To address this issue, we have recently developed a model system for studying protein dimerization that has allowed us to delineate the principles that govern induced protein oligomerization by a small molecule. Our hope is to ultimately apply our understanding of these processes to the design of molecules capable of selective cell surface receptor activation. In addition, we are applying these concepts to the design of novel chem-protein based biopolymers.

3) Mechanistic and Structural Studies of Biocatalysis Arylamine N-acetyltransferases (NATs) are versatile enzymes that catalyze both the conversion of carcinogenic arylamines to arylamides and the bioactivation of arylhydroxylamines and arylhydroxyamic acids to electrophilic cancer causing metabolites. Our laboratory, in collaboration with Dr. Patrick E. Hanna, has recently cloned, expressed, and purified the hamster monomorphic and polymorphic NAT isozymes and demonstrated a novel catalytic mechanism for this enzyme. Currently we are conducting investigations by chemical, molecular genetic, NMR and x-ray cyrstallographical techniques in order to fully characterize the enzymatic role of these proteins in xenobiotic bioactivation.

Selected Recent Publications

• Drontle, Daniel P. and Wagner, Carston R. Wagner, "Nucleoside Amino Acid Phosphoramidates as an Effective Pronucleotide Strategem," Mini-Reviews in Medicinal Chemistry, 4, 409-419 (2004).
• Kim, Jisook, Griesegraber, George, W., Chou, Tsui-fen., and Wagner, Carston R., "Direct Measurement of Nucleoside Monophosphate Delivery from a Phosphoramidate Pronucleotide by Stable Isotope Labeling and LC-ESI-MS/MS,' Molecular Pharmaceutics 1, 102-11 (2004).
• Wang, Haiqing, Vath, Gregory, Gleason, Kara J., Hanna, Patrick E., and Wagner, Carston R., "Probing the Mechanism of Hamster Arylamine N-acetyl Transferase 2 Acetylation by Active Site Modification, Site-directed Mutagenesis, and Pre-steady State and Steady State Kinetic Studies" Biochemistry, 43, 8234-8246 (2004).
• Guo Zhijun, Vath, Wagner, Carston R., and Hanna, Patrick E "Mass Spectrometric Investigation of the Mechanism of Inactivation of Hamster Arylamine N-Acetyltransferase 1 by N-Hydroxy-2-Acetylaminofluorene"Chemical Research in Toxicology, 17, 276-286 (2004).(Paper selected for CRT cover)
• Carlson, Jonathan C. T., Kanter, Aaron; Thuduppathy, Guruvasuthevan. R., Cody, Vivian, McIvor, R. Scott and Wagner, Carston R., "Designing Protein Dimerizers: The Importance of Ligand Conformational Equilibria,"Journal of the American Chemical Society, 125, 1501-1507 (2003).