Department of Medicinal Chemistry

• B.A. 1966, Southern Illinois University at Carbondale
• Ph.D. 1970, Stanford University
• NATO Fellow, Cambridge University, 1970-71

Research Interests

COBRE Center in Protein Structure and Function.

Drug metabolism: enzyme mechanisms and inhibition.

Chemical mechanisms of cytotoxicity.

Protease inhibitors.

COBRE Center in Protein Structure and Function.

In addition to the research activities listed below, Dr. Hanzlik is the Principal Investigator and Director of a multi-campus NIH Center of Biomedical Research Excellence in Protein Structure and Function. (Click here for further information)

Drug metabolism: enzyme mechanisms and inhibition.

A major interest in the Hanzlik research group is understanding a fascinating family of enzymes known as the cytochromes P450. Some of these enzymes metabolize drugs and foreign compounds while others catalyze biosynthetic processes involving steroid hormones and eicosanoids. We investigate how P450 enzymes hydroxylate their substrates, often in highly specific ways. Carefully designed "probe" molecules are synthesized and their metabolism is investigated using state-of-the-art analytical methods. Stable- and radioisotope labeling and kinetic isotope effects are also often employed. (Click here for more details and references)

Chemical mechanisms of cytotoxicity.

P450 enzymes can also "bioactivate" many simple organic compounds to form chemically-reactive cytotoxic metabolites. Examples include bromobenzene, thiobenzamide, the analgesic drug acetaminophen, the herbicide molinate, and the general anesthetic halothane. Biotransformation of these and many other agents by P450 enzymes sometimes generates chemically-reactive metabolites which express their reactivity by reacting with cellular proteins, ultimately injuring the cell. A major objective of our group is the identification of important target proteins and the structures of the protein-metabolite adducts formed by a number of simple cytotoxic compounds. Adducted proteins are located on 2D gels by autoradiography or western blotting and identified, along with their adducts, by modern methods of proteomics based on MALDI-TOF-MS and HPLC/MS/MS. (Click here for more details and references)

Although this project has ended, we have also worked on the design, synthesis and evaluation of inhibitors for cysteine protease enzymes. Cysteine proteases play unique biological roles in virus-infected mammalian cells, certain cancer cells, parasitic protozoa, and in processes leading to programmed cell death (apoptosis). Although their biology is diverse, cysteine proteinases share a common mechanism of action, and the lack of effective therapeutic agents in these areas creates an opportunity for novel approaches to drug design. (Click here for more details and references)