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Scientific Report 2004


Chemistry




Chairman’s Overview


As the “central science,” chemistry stands between biology and medicine and between physics and materials science and provides the crucial bridge for drug discovery and development. But chemistry has a much more profound and useful role in science and society. It is the discipline that continually creates the myriad of new materials that we all encounter in our everyday lives: pharmaceuticals, high-tech materials, polymers and plastics, insecticides and pesticides, fabrics and cosmetics, fertilizers, and vitamins—basically everything we can touch, feel, and smell.

Chemists at Scripps Research focus on chemical synthesis and chemical biology, the most relevant areas to biomedical research and materials science. The members of our faculty are distinguished teacher-scholars who maintain highly visible and independent research programs in areas as diverse as biological and chemical catalysis, synthesis of natural products, combinatorial chemistry, molecular design, supramolecular chemistry, chemical evolution, materials science, and chemical biology. The chemistry graduate program attracts some of the best-qualified candidates from the United States and abroad. Our major research facilities, under the direction of Dee H. Huang (nuclear magnetic resonance), Gary Siuzdak (mass spectrometry), and Raj Chadha (x-ray crystallography), are second to none and continue to provide crucial support to our research programs. In addition, the Mabel and Arnold Beckman Center for the Chemical Sciences constantly receives high praise from visitors from around the world for its architectural design and operational aspects, both highly conducive to research. The death this year of Arnold Beckman was difficult for all of us, but his legacy to chemistry lives on in these halls.

Research in the Department of Chemistry goes on unabated, establishing international visibility and attracting attention, as evidenced by numerous lecture invitations, visits by outside scholars, and headline news in the media. The Institute for Scientific Information ranked Scripps Research as the top institution in the world in terms of high-impact papers in chemistry for the 1994–1996 period and, as of 2003, now names 5 members of the chemistry department as highly cited researchers (in the top 100 worldwide); 2 of the 5 are among the top 25.

Dr. Lerner and his group continue to make advances in catalytic antibodies, with new antibodies that catalyze important synthetic and biological reactions and novel applications in chemical synthesis. The research of the group recently expanded to include the fundamental chemistry of the polyoxygen species. Members of the Sharpless group continue endeavors to discover and develop better catalysts for organic synthesis and to construct, through innovative chemistry and biology, libraries of novel compounds for biological screening.

Scientists in the La Jolla–based Eschenmoser group advance in experimental studies on the chemical etiology of nucleic acid structure by investigating nucleic acid alternatives that have novel backbone structures unrelated to the canonical phosphodiester-based oligonucleotide systems. Members of my group continue explorations of chemical synthesis and chemical biology, focusing on the total synthesis of new anticancer agents, antibiotics, marine-derived neurotoxins, antimalarial compounds, antifeedant agents, other biologically active natural products; solid-phase synthesis; and combinatorial chemistry.

Members of the Rebek group devise biomimetic receptors for studies in molecular recognition. These include molecules that bind neurotransmitters and membrane components. Larger host receptors can surround 3 or more molecular guests and act as chambers where the chemical reactions of the guests are accelerated.

Scientists in the Schultz laboratory continue to expand the genetic code. Using unique triplet and quadruplet codons, they have genetically encoded more than 30 novel amino acids in bacteria, yeasts, and mammalian cells. Dr. Wong and his group further advance the fields of chemoenzymatic organic synthesis, chemical glycobiology, and the development of enzyme inhibitors. A new strategy for the glycoprotein synthesis has been developed. The programmable 1-pot synthesis of oligosaccharides developed by this group has been further used in the assembly of glycoarrays in microtiter plates for study of saccharides and aminoglycosides that bind to proteins and RNA, respectively. This group also developed new inhibitors of glycosyltransferases, sulfotransferases, and the HIV protease.

Members of the Boger group continue their work on chemical synthesis; combinatorial chemistry; heterocycle synthesis; anticancer agents, such as fostriecin and yatakemycin; and antibiotics, such as vancomycin, teicoplanin, and ramoplanin. Scientists in the Janda laboratory focus on the impact of organic chemistry in specific biological systems. Their targeted programs span a wide range of interests, from drug addiction to biological and chemical warfare agents to catalytic antibodies to combinatorial chemistry. Their recent achievements include the discovery that a secondary nicotine metabolite can inhibit the formation of the fibrils characteristic of Alzheimer’s disease, the biological validation of a common quorum-sensing molecule, and a high-throughput assay based on a blue fluorescent antibody sensor.

Dr. Ghadiri and members of his laboratory are making significant contributions in the design and study of a new generation of antimicrobial agents, based on self-assembling peptide nanotube architecture, to combat multidrug-resistant infections. In addition, they continue to make novel contributions in several ongoing basic research endeavors, such as design of biosensors, molecular computation, design of self-reproducing systems, understanding the origins of life, and design of emergent chemical systems.

Dr. Finn and his group are pioneers in the use of virus particles as chemical reagents and building blocks for nanochemical structures. This effort is directed toward the development of new diagnostics for disease and catalysts for organic reactions. Members of the Finn laboratory also develop and investigate new organic and organometallic reactions and use these processes to synthesize biologically active compounds.

Research by members of the Kelly group emphasizes the role of protein conformational changes in neurodegenerative disease and the alteration of these processes through the design and synthesis of small molecules. These scientists also take advantage of the power of chemistry and biology to study β-sheet folding. An emerging interest is self-assembling biomaterials made from peptides and proteins.

Researchers in the Romesberg laboratory are using diverse techniques ranging from bioorganic and biophysical chemistry to bacterial and yeast genetics to understand and manipulate evolution. Major efforts include the design of unnatural base pairs and the directed evolution of DNA polymerases to efficiently synthesize unnatural DNA containing the base pairs; using spectroscopy to understand biological function and how it evolves; and understanding how induced and adaptive mutations contribute to evolution in eukaryotic and prokaryotic cells.

Dr. Baran and his group have been pushing the envelope in synthetic organic chemistry. In less than a year, they have developed practical chemical solutions to the longstanding (>20 years) synthetic challenges posed by the rare marine natural products sceptrin and ageliferin. Inspiration from marine natural products also led to the invention of new methods for the practical synthesis of indoles and pyrroles (heterocycles embedded in a plethora of medicinal agents).

Researchers in the Kolb group are using a set of reliable and modular organic transformations, called click chemistry, to develop inhibitors of disease-related proteins. In the “in situ” variant of this approach, the biological target is used to assemble its own inhibitors from monomeric reagents that best fit into the protein’s binding pockets. This target-templated approach, which does not require laborious synthesis and screening of large libraries of compounds, has been successfully applied to acetylcholinesterase, carbonic anhydrase, and HIV protease.

The Frontiers in Chemistry Lecturers (15th Annual Symposium) for the 2003–2004 academic year were K. Barry Sharpless, Scripps Research; Samuel J. Danishefsky, Sloan Kettering Institute for Cancer Research and Columbia University; David A. Evans, Harvard University; and Julius Rebek, Jr., Scripps Research. Professor William Jorgensen, Yale University, also visited the department this year as the Bristol-Myers Squibb Lecturer.

 


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

Nicolaou Web Site