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Department of Chemistry

Members of TSRI's Department of Chemistry work at the interface of chemistry and biology. They conduct research in chemical synthesis, chemical biology, catalysis, combinatorial chemistry, and molecular design through interdisciplinary research that aims to discover the fundamental workings of human biology and to facilitate the drug discovery process. The faculty has an international reputation for excellence and includes several members of the National Academy of Sciences. Three members of the faculty are named in the Institute for Scientific Information (ISI) list of the world's most cited authors, comprising less than one half of one percent of all publishing researchers.

In addition, W.M. Keck Professor of Chemistry K. Barry Sharpless was awarded the 2001 Nobel Prize in Chemistry with William S. Knowles and Ryoji Noyori for his contributions to the development of the selective production of chiral molecules with the proper right- or left-"handedness"—the structural characteristic of a molecule that makes it impossible to superimpose on its mirror image. Proteins, DNA, and carbohydrates are all chiral molecules: without the correct handedness, they will not function properly. Many drugs must also be of the correct chirality; indeed, in some cases, the molecules with the wrong chirality can be toxic.

The design of drugs to address age-related illnesses like Alzheimer’s disease is a crucially important endeavor in science today, and Sharpless has pioneered a new type of synthetic chemistry, called click chemistry, which can be used as a valuable tool for the discovery of drugs to block the activity of enzymes relevant to diseases like Alzheimer’s. Unlike other methods, click chemistry uses the target enzymes themselves to select the final synthetic step and catalyze the final reaction that creates the inhibitors of those enzymes.

Also creating a need for new drugs are antibiotic-resistant bacteria, which pose a growing public health threat worldwide. The World Health Organization estimates the total cost of treating all hospital-borne antibiotic-resistant bacterial infections to be around $10 billion a year. Several investigators in the department tackle the problem of drug design using the approach of total synthesis of architecturally novel and biologically active natural products. Synthetic methods seek to make, in abundance and from simpler precursors, compounds that cannot be found abundantly in nature—architecturally complex molecules that were often designed by nature to do exactly what we need them to do, such as kill bacteria. Several small-molecule anticancer agents and antibiotics have been synthesized to date, and numerous efforts are underway to synthesize other antitumor, antibiotic, and antiviral agents.

As a by-product of the total synthesis effort, faculty members hope to develop novel synthetic strategies and create new synthetic technologies, which are important for the field of organic chemistry. They have also designed thousands of synthetic precursors and other novel chemical compounds that have allowed them to construct chemical libraries, which can be used for screening to find potential lead compounds that could be used in drug design.

Other members of the department carry out synthesis using carbohydrate structures. This technique involves placing a large number of specific chemical building blocks into a reaction vessel and then making sequential chemical reactions in the soup. The final products—antibiotics and enzyme inhibitors—depend entirely on the particular reaction scheme followed.

In nature, only the L-form of amino acids (left-handed) are used to make peptides, or proteins, but there are no such constraints in the laboratory. In another approach to antibiotic resistance, cyclic peptides were built by putting alternating right- and left-handed amino acids together into short six- and eight-amino acid chains, and then joining the two ends of the chain together. Because of their unusual alternating right- and left-handedness, these "cyclic" peptides are round and flat, like a donut.

By altering the amino acids from which the cyclic peptides were built, the peptides were designed so that they insert themselves into bacterial cell walls in a highly specific way. Inside the walls of a bacterium, these cyclic peptides spontaneously self-assemble into nanotubes, like donuts on a string, and poke holes in the membranes of bacteria, killing them.

Several researchers in the department are unraveling the complexity of living systems. One group pursues research on the fundamentals of how molecules fit together or recognize each other by synthesizing molecules that are self-complementary and can assemble to surround small targets. These assemblies are used to accelerate reactions, stabilize reactive intermediates, and probe the events involved in molecular recognition.

Another group of researchers has developed a general method to make the bacterium Escherichia coli incorporate the novel amino acid O-methyl-tyrosine into proteins site-specifically and with high fidelity. This is the first of several new amino acids the team is working on. Also called "unnatural" because they are not among nature's original 20, these novel amino acids have the same backbone as the 20 standard amino acids but different side chains. Some have just slightly altered chemical structures and others have new functional groups added. In proteins, these differences may alter everything from structure and folding to activity. Certain "designer" side chains may even impart novel functionality.

Another team in the department studies the chemical origins of nucleic acid structure by investigating systems that make use of alternative, but structurally related, nucleic acids.

In another avenue of research, two faculty members are collaborating to develop chemical methods that can be used to identify proteins whose activity is biologically important—a method called "active site proteomics." Proteomics is a relatively new field that attempts to further the information available from the human genome by examining how and where genes are expressed inside a cell to make proteins. What is often the predominant question in cancer research, for example, is which of these proteins are active—a question that active site proteomics seeks to answer by reading changes in protein activity directly and enabling visualization of the protein activity in a living cell by "interrogating" a protein's active site.

Finally, a very important area of research within the department involves the design and use of antibodies in novel ways. Catalytic antibodies are human immunoglobins that have useful chemical activity, in addition to their antigen specificity, that can catalyze important reactions.