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Scientific Report 2008

The Skaggs Institute for Chemical Biology

Director’s Overview

for Chemical Biology was established in 1996 by a spectacular gift from L.S. "Sam” Skaggs. During the past 12 years, more than 100 million dollars has been awarded in research support for members of the Skaggs Institute. Currently, the funding supports 31 principal investigators, 99 postdoctoral fellows, and 61 graduate students. The mission of the institute is to conduct science that leads to new medicinal agents to relieve suffering. Here I describe some of the progress made by members toward these goals. More details can be found in the individual reports.

Stephen Mayfield has used his genetically modified algae to produce carbon-neutral liquid biofuels, a splendid result at a time when fossil fuels reserves are dwindling. Algae can produce biomass at a rate higher than terrestrial plants do and can be used to synthesize therapeutic proteins. In short, algae are a versatile and renewable energy source.

M. Reza Ghadiri has developed new cyclic peptide mimetics as scaffolds to present amino acid side chains involved in protein-protein interactions. Using the triazole as a peptide bond surrogate, he has developed useful bioactive probe molecules that imitate the 3-dimensional pharmacophore of naturally occurring tetrapeptides.

M.G. Finn continues to modify the surfaces of intact viral capsids by using, among other methods, click chemistry. These modifications have been used to display carbohydrates on the exterior capsid surface as well as polycations that efficiently inhibit the action of heparin.

Jeff Kelly, the new chairman of the Department of Molecular and Experimental Medicine, is studying the role of amyloidosis in diabetes. Deposits of amylin in the pancreas are related to the compromised function of these secretory cells that characterize the disease.

Jamie Williamson has developed a powerful enzymatic synthesis of nucleotides such as adenosine triphosphate. The process involves 28 enzymes but can be carried out in 60% yield starting from glucose, carbon dioxide, ammonia, and serine. The synthesis is ideal for isotopically labeled products for use in nuclear magnetic resonance analysis of the structure of proteins and nucleic acids.

Ullrich Müller is studying the hair cells of the inner ear that are the principal mechanosensors for the detection of sound and head movement. He is unraveling the molecular composition of the mechanotransduction machinery in these cells by identifying the genes that control their functions.

Ehud Keinan has proposed a general synthetic strategy of using a simple pentagonal core to produce chemical capsids that are approximately the size of spherical viruses. He has modeled the assembly and dissociation of these systems under controlled environmental conditions and has made progress in synthesizing the molecules that have the proper shapes and recognition surfaces.

Dale Boger and his group work on inhibiting enzymes that control natural painkillers such as anandamide. They have developed synthetic molecules that are more efficient than ibuprofen and are similar to morphine in potency as analgesics in neuropathic pain.

Carlos Barbas used a reductionist approach on catalytic antibodies to identify the key features of their catalytic abilities. He has shown that simple chiral amines can be nearly as effective in asymmetric catalysis for many reactions that make complex carbon-carbon bond arrays.

Geoffrey Chang has developed x-ray crystallography to characterize molecules involved in multidrug resistance. These molecules transport small drug molecules from inside the cell to outside and are involved in the efflux of antibiotic compounds. The goal is to develop inhibitors of the process that can be used in the treatment of infections.

Gerald Joyce, dean of the Scripps Research faculty, has developed "evolution on a chip.” This method combines a large population of RNA molecules and computer controlled microfluidic chips that allow adaptation to occur through hundreds of cycles in a few days. He has also developed small molecules that can trigger RNA enzymes to catalyze their own formation: molecular replication.

Kim Janda is working to manipulate the chemical biology of cell-to-cell signaling known as quorum sensing. His findings have applications in controlling virulence and infectivity of bacterial and other microbial agents.

Peter Schultz continues to add more amino acids to the repertoire of synthetic biology. Proteins made from amino acids with an expanded genetic code can confer an evolutionary advantage and improved pharmacologic properties. These proteins are directed to applications in biomedical technology.

Ian Wilson continues to study those few potent but broadly neutralizing antibodies that recognize HIV type 1. The elusive goal is still to develop the structural information in these complexes for use in a vaccine.

Lisa Stowers studies neural circuits that underlie innate behavior. She uses olfactory stimulus in rodents to identify the neurons involved. Her studies suggest that maternal-infant behavior in rodents is also triggered by olfactory mechanisms.

In prebiotic chemistry, a debate continues on the relative importance of replication vs metabolism in the origins of life. Albert Eschenmoser is making progress on both of these fronts. He and his group make use of ever-simplified backbones derived from glyceric acid for replication and explore the chemistry of glyoxylate for metabolism.

Chi-Huey Wong has invented a new method for the ligation of peptides in which attached sugars are used as delivery vehicles. The intent is to optimize the methods to achieve the total synthesis of therapeutic glycoproteins as single isomers.

In my own research group, we continue to explore the behavior of molecules in small spaces. These arrangements, known as encapsulation complexes, isolate molecules from the medium and expose unusual behaviors, shapes, and reaction intermediates that cannot be seen in solution.

Among the honors bestowed on the Skaggs investigators, 2 were particularly noteworthy. Peter Wright, chairman of the Department of Molecular Biology, was elected to the National Academy of Science, and Tamas Bartfai, Chairman of the Molecular and Integrative Neurosciences Department, was elected to the Swedish Academy of Sciences. Members of the Skaggs Institute won numerous national and international prizes and earned many honorary degrees in the past year.

My colleagues and I are grateful for the continued support of the Skaggs Institute for Research. They provide generous funding for basic science at the interface of chemistry and biology.


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

Skaggs Institute Reports

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