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The Skaggs Institute
for Chemical Biology


Scientific Report 2006




Director’s Overview


The Skaggs Institute for Chemical Biology was established in 1996; we have now completed our first decade. During this time, the generous endowment from the Skaggs family has supported more than 30 principal investigators and some 500 postdoctoral fellows and graduate students. The financial support from the Skaggs Institute has been acknowledged in more than 2000 publications, and the Institute has gained a worldwide reputation for excellence in research. A few of the highlights of research from the past year are given here; the individual reports from the principal investigators are presented elsewhere in this volume.

In a multidisciplinary measure, researchers in the laboratories of Geoffrey Chang and M.G. Finn are designing inhibitors to biological molecules that cause resistance to cancer drugs. The scientists take advantage of x-ray structures of drug “antiporters” and of electron cryomicroscopy to study how the molecules change shape as they mediate drug resistance. Steve Mayfield and his group are using algae as a system for production of therapeutic proteins. Specifically, using material obtained from soldiers who had been vaccinated against anthrax, they produced a human antibody to anthrax. Other antibodies are targeted as anticancer agents, particularly therapeutic proteins for treatment of childhood lymphomas. Chi-Huey Wong and his research group use enzymes as reagents for organic synthesis. One of their ultimate goals is to use enzymes to modify proteins with sugars on the surfaces of the proteins that will lead to vaccines against HIV disease, influenza, and breast cancer. This approach is complemented by a new ligation method in which a sugar derivative accelerates the coupling of protein fragments.

Paul Schimmel and members of his laboratory continue to investigate the components of the apparatus that converts genetic information into proteins. They found that the enzymes that attach amino acids to tRNA have additional activities as cell signaling proteins. These cytokines are needed for control of blood vessel growth and inflammation, and control of these signaling activities may eventually lead to therapies. Peter Wright and his colleagues are studying protein-protein and protein–nucleic acid interactions in solution. Specific targets include the transcriptional coactivators that have been implicated in human diseases such as leukemia, cancer, and mental retardation.

Studies of small-molecule agents that bind nucleic acids are one of the projects of Dale Boger and members of his laboratory. These researchers have synthesized naturally occurring antitumor agents and showed that the natural compound and its mirror image are equally effective at covalent binding to nucleic acids. Another project involves the redesigning of the vancomycin antibiotic to overcome microbial resistance to this drug. This exercise in molecular recognition has led to a new structure that is 100-fold more effective at binding to resistance peptides. Carlos Barbas and his group focus on strategies to produce antibodies for use in organic synthesis that form or break carbon-carbon bonds. The antibodies are evolved by using novel recombinant strategies. Dr. Barbas also spearheads an effort to use small organic molecules with enzymelike activities for organic synthesis.

Ernest Beutler and scientists in his group are studying mechanisms involved in checkpoints that maintain genome stability. These checkpoints are principal defense mechanisms against malignant phenotypes and forces for tumor growth. Elizabeth Getzoff and the members of her laboratory are characterizing the mechanisms of light-induced protein activities, particularly in the cryptochrome flavoproteins that are components of the circadian clocks in animals and humans.

Jamie Williamson and his colleagues use nuclear magnetic resonance to study large molecules such as viral capsid proteins in solution. The nuclear magnetic resonance spectra reveal mobile protein segments that cannot observed by using x-ray or electron microscopy methods. Ian Wilson and his group also pursue the crystallographic characterization of influenza virus glycoproteins. They intend to improve the potency of antiviral drugs by solving the structure of the neuraminidase, the viral coat protein involved in the 1918 influenza pandemic.

K.C. Nicolaou and the researchers in his group have made great progress in the synthesis of several biologically active molecules, including antitumor agents from the cytoskyrin family, marine-derived antibiotics, and marinomycins. K. Barry Sharpless and Valery Fokin and their colleagues continue to develop click chemistry, extremely versatile reactions that drive spontaneous selective and irreversible linkages between molecular building blocks. These scientists are using these reactions for rapid exploration of chemical space.

Richard Lerner and Subhash Sinha and their associates develop antibodies for selective chemotherapy. The antibodies involve drug conjugates and prodrugs that target cell-surface receptors and prostate-specific membrane antigen. The antibodies convert prodrugs into active molecules at the sites where the molecules are most needed. Kim Janda and his group explore the other activities of botulinum neurotoxins, including applications in multiple sclerosis, stroke, and migraine. Molecules that can activate the toxins would lead to lower dosages and reduce the immune response in these applications.

Tamas Bartfai and members of his laboratory study the temperature regulation of mammals; using transgenic methods, these researchers have developed a new animal: “the cool mouse.” These transgenic mice have their thermostat effectively lowered, resulting in less energy expenditure and longer life times for the animals.

Jeffrey Kelly and his group are studying protein folding and misfolding involved in diseases such as Alzheimer’s, Parkinson’s and Gaucher disease. They found that oxidative cholesterol metabolites can modify amyloid peptide and accelerate the precipitation associated with Alzheimer’s disease. Members of my own group continue the study of molecules in extremely small spaces, how the molecules interact when confined to close range. This research has led to newly discovered stereochemical properties and a spring-loaded device for nanomachinery.

All of us are thrilled to be associated with the Skaggs Institute for Chemical Biology and are grateful for the research opportunities that are provided by the support of the Skaggs family. We look forward to our second decade.

 

Julius Rebek, Jr., Ph.D.
Director and Professor

Rebek Web Site