News and Publications

Chemistry

K.C. Nicolaou, Ph.D., Chairman

embers of the 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.

This year, three members of the faculty, Drs. K.C. Nicolaou, K. Barry Sharpless, and Chi-Huey Wong, were included in the Institute for Scientific Information (ISI) list of the world's most cited authors in the past 20 years, comprising less than one half of one percent of all publishing researchers. According to ISI, the list identifies "individuals, departments, and laboratories that have made fundamental contributions to the advancement of science and technology in recent decades."

Shortly after this recognition, Sharpless won the 2001 Nobel Prize in Chemistry. The award also was presented to William S. Knowles, formerly of Monsanto, and Ryoji Noyori of Nagoya University in Japan, for "the development of catalytic asymmetric synthesis." Sharpless contributed innovations 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 it on its mirror image. Proteins, DNA, and carbohydrates are all chiral molecules: without the correct handedness, they will not function as the basic molecules of life. Many drugs must also be of correct chirality; indeed, in some cases, the molecules with the wrong chirality can be toxic. One problem in designing pharmaceuticals is that a non-selective synthesis will yield both chiral forms, which may be hard or prohibitively expensive to separate.

In 1980, Sharpless reported a breakthrough in synthesizing chiral molecules with a method that is now used routinely, and he has since developed other methods that have revolutionized organic chemistry by transforming asymmetric synthesis from nearly impossible to routine. Sharpless's methods allow for the manufacture of safer and more effective antibiotics, anti-inflammatory drugs, heart medicines, and agricultural chemicals because they allow chiral forms to be synthesized selectively, rather than separated later.

COMBATING ANTIBIOTIC RESISTANCE

Chirality also played a role in a breakthrough reported by another laboratory this year. M. Reza Ghadiri, Ph.D., designed a broad approach for designing drugs to combat such problems as infections with antibiotic-resistant bacteria. Ghadiri and his coworkers created a class of biological polymers known as cyclic peptide nanotubes, which stack inside the cell membranes of bacteria and poke holes in their membranes, killing the bacteria.

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. Ghadiri and his colleagues built cyclic peptides 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, Ghadiri and his colleagues were able to design them 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.

These nanotube stacks have demonstrated strong bactericidal activity both in the test tube and in living tissue against a number of deadly pathogens, including multidrug-resistant Staphylococcus aureus, one of the most common hospital-acquired infections. Antibiotic-resistant bacteria are a growing public health threat worldwide, and the World Health Organization estimates the total cost of treating all hospital-borne antibiotic-resistant bacterial infections is around $10 billion a year.

ACTIVE SITE PROTEOMICS

In another avenue of research in the Department of Chemistry, two faculty members are collaborating to develop chemical methods that can be used to identify proteins whose activity is biologically important. The investigators, Benjamin Cravatt, Ph.D., and Erik Sorensen, Ph.D., call this method "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. Insight into how the genome is expressed and how it is controlled can be found, for example, by comparing the expression profiles of two different cell types from different tissues, organisms, stages of development, or disease states.

However, at any given time cells will express more proteins than they actually use, and the proteins that are the most important may also be the ones that are the least expressed. 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 giving a visualization of the protein activity in a living cell by "interrogating" a protein's active site.

Cravatt and Sorensen have demonstrated that active site proteomics gives information on certain classes of enzymes. The researchers are currently developing broad chemical probes to apply the concept to a large menu of enzyme families. By characterizing the enzymes collectively rather than individually, a large number of enzymes in a cell can be profiled with only a few probes.

One of the principal uses of these probes will be to generate differential maps of cancerous and healthy cells. These maps should show the differences in activity between enzymes in the two types of cells -- and may give clues that will be useful in developing cancer therapies.

Encoding proteins from DNA is one of the most fundamental requirements for life, since proteins do much of the microscopic work of the cell and make up a large part of the physical structure of cells and tissue. But one of the great unanswered questions of evolutionary biology is why there are only 20 amino acids in nature.

Peter Schultz, Ph.D., and his laboratory have 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 they are 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.

Proteins with novel amino acids may have enhanced or emergent properties and would be useful tools for studying protein interactions and cellular functions. Furthermore, having a bacterial expression system will make them trivial to produce on a massive scale.

The Department of Chemistry also continues to distinguish itself in the field of total synthesis of architecturally novel and biologically active natural products. By targeting these products, faculty members such as Drs. K.C. Nicolaou, Dale L. Boger, and Chi-Huey Wong hope to develop novel synthetic strategies and to create new synthetic technologies. Synthetic methods are crucial for drug development because they seek to take commercially available precursor chemicals and make, in abundance, compounds that cannot be found abundantly in nature. Indeed, several efforts are underway to synthesize antitumor, antibiotic, and antiviral agents. And almost every new synthesis may help facilitate further biomedical research.