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Skaggs Institute for Chemical
Biology
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The Skaggs Institute for Chemical Biology at TSRI was established in 1996 by Aline and Sam Skaggs with a commitment of $100 million through the Skaggs
Institute for Research and their family foundation, the ALSAM Foundation.
The Skaggs Institute for Chemical Biology at TSRI was established
by Aline and Sam Skaggs with a commitment of $100 million through
the Skaggs Institute for Research and through their family foundation,
the ALSAM foundation.
Skaggs investigators have determined the structures and functions of many proteins and nucleic acids,
particularly those involved in cancer and diseases of the immune system. For
instance, one lab uses x-ray crystallography to determine the structures of
molecules involved in diabetes, anemia, and HIV disease. Another uses nuclear
magnetic resonance to study protein-protein and protein-nucleic acid
interactions in solution. Targets for therapeutic intervention include
macromolecules involved in leukemia, cancer, and mental retardation.
Other investigators are looking at the structural details and folding pathways of RNA molecules, including RNA
enzymes, the ribozymes, and the complex machinery of the ribosome, the site
where proteins are manufactured inside living cells.
Proteins are of particular interest to several investigators who work in the new field of proteomics, which extends
the information from the human genome by studying how the genes are actually
expressed in various tissues under normal conditions or in disease states. For
instance, what genes are expressed in particular regions of the brain during
waking and after sleep deprivation? What genes are expressed in cancer cells?
In sleep, pain sensitivity, and thermoregulation? Moreover, two Skaggs
investigators are developing probes to analyze which proteins are active in
particular tissues and disease states.
With state of the art equipment TSRI's labs are the best
in the country. |
Skaggs investigators have discovered new catalysts for chemical reactions of interest to medicinal
chemistry, and several of the groups at Skaggs are using antibodies to carry
out chemical catalysis. They have developed efficient systems for the synthesis
of antibodies, discovered new antibodies that release proven anticancer drugs
from the drug precursors within living organisms, and found that all antibodies
can convert oxygen into hydrogen peroxide, which may be important in
understanding how antibodies evolved.
The actual connectivity of proteins is being scrutinized by a Skaggs team that uses chemical ligation to
tie the polypeptide chain into knots. Another team addresses cancer by studying
nucleic acid repair enzymes. And a third has determined the solid-state
structures of human enzymes involved in the processing of nitric oxide, a
biological messenger of blood pressure regulation, blood clotting, and
neurotransmission.
Living systems and their properties are also investigated by a number of Skaggs researchers. One group
has made progress on purely synthetic molecules that indicate how molecular
information and nonlinear catalysis can lead to self-organization and emergent
properties generally associated with living systems. Another investigates the
origins of nucleic acid structure and has discovered an alternative nucleic
acid based on threose that can base pair and share information with RNA and
DNA. And another uses directed molecular evolution to create nucleic acid
enzymes, including ones that can cleave RNA or DNA molecules involved in
multiple sclerosis.
Two laboratories have paved the way toward an expanded genetic code by designing separate methods for
engineering bacteria to encode unusual amino acids into proteins. These
techniques can be used to design completely novel proteins to probe the basic
biology of various molecules and organisms.
The fundamentals of how molecules fit together and how they recognize each other is being pursued by another
research group, which is synthesizing self-complementary molecules that
assemble completely surrounding small targets. These assemblies are used to
accelerate reactions, stabilize reactive intermediates, and probe weak intermolecular
forces.
Another investigation produces structure-based small molecules for intervention in neurodegenerative diseases,
especially those involving the build-up of amyloid plaques in the brain.
Two Skaggs research groups successfully completed the total synthesis of vancomycin, which acts as the
last line of defense against life-threatening antibiotic-resistant infections.
The last decade has seen the emergence of a strain of Staphylococcus aureus that is resistant to vancomycin's mode of action, in which
the molecule binds to the cell wall of a bacteria and arrests its growth. Staphylococcus
aureus's resistance involves a subtle, single-atom change in the components of the growing cell wall. The resistance
is encoded in the DNA of the organism and this DNA is mobileÜit can be passed
from one bacterial cell to another, similar to the way in which penicillin
resistance spreads.
One research group at The Skaggs Institute is positioned to overcome this resistance by making complementary
changes on the synthetic vancomycin, hoping to restore the binding to the bacterial cell wall and overcome the resistant bacteria's defense. Another is
using the methods known as combinatorial chemistry to prepare and screen a large number of vancomycin-like molecules for antibiotic activity in a short
time. A number of potent antibiotics have already been discovered using this approach.
A different approach to the problem of antibiotic resistance is being pursued by another laboratory, which
is devising programmable, automated syntheses of libraries of oligosaccharides, which are sugar molecules involved in cell-surface recognition. These libraries
can then be screened for new antibiotics, like ones that target bacterial RNA, for example.
The Skaggs Institute for Chemical Biology also seeks to provide a nurturing environment for the next generation
of research scientists. Each year it supports more than 200 postdoctoral researchers and an average of 40 graduate studentsÜThe Skaggs Institute's most
important assets.
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Skaggs Institute for Chemical Biology
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Skaggs Institute Scientific Report 2001
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