The Skaggs Institute
for Chemical Biology
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.
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