Scientific Report 2006

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 areas most relevant 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 both 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.

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. As of 2005, the Institute for Scientific Information ranked 3 members of our department as highly cited researchers (in the top 100 worldwide); 2 of the 3 are among the top 51 positions.

Richard 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 group’s research has recently expanded to include the fundamental chemistry of the polyoxygen species.

Barry Sharpless and his 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 Albert Eschenmoser’s La Jolla-based group advance their experimental studies on the chemical etiology of nucleic acid structure by investigating nucleic acid alternatives that have novel backbones and recognition elements unrelated to the canonical phophodiester-based oligonucleotide systems.

Members of my own 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, and other biologically active natural and designed molecules.

The members of Julius Rebek’s 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. The group synthesizes small molecules that act as protein helix mimetics for pharmaceutical applications.

Peter Schultz and his group have continued to expand the number of genetically encoded amino acids to include fluorescent, photocaged, metal binding, thioester, sulfated, and long-chain alkane side chains. They have also adapted this technology to mammalian cells and are applying it to a number of basic and applied problems in cell biology. In addition, they have used cell-based screens to identify small molecules that selectively differentiate and expand embryonic and adult stem cells and reprogram lineage-committed cells, as well as novel genes that control cell cycle, cell migration, and developmental pathways.

Chi-Huey 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 synthesis of glycoproteins has been developed. The programmable 1-pot synthesis of oligosaccharides developed by this group has been further used in the assembly of glycoarrays for study of saccharides that bind to proteins. This group also developed new probes to study glycosyltransferases and their role in cancer.

Members of Dale Boger’s group continue their work on chemical synthesis; combinatorial chemistry; heterocycle synthesis; anticancer agents such as vinblastine, fostriecin, and yatakemycin; and antibiotics such as vancomycin, teicoplanin, and ramoplanin.

Scientists in Kim Janda’s laboratory are focusing on the impact of organic chemistry in specific biological systems. Their targeted programs span a wide range of interests from immunopharmacotherapy to biological and chemical warfare agents to filarial infections, such as "river blindness," to quorum sensing in bacteria. Their recent achievements include the discovery of a secondary nicotine metabolite that alters retinoid homeostasis, a critical component of vision and growth; small molecules that "superactivate" botulinum neurotoxin; and a virus-based system that can degrade cocaine in the central nervous system.

Reza Ghadiri and his group 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 biosensor designs, molecular computation, design of self-reproducing systems, understanding the origins of life, and design of emergent chemical systems.

M.G. Finn and his group have pioneered 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 Dr. Finn’s laboratory also develop and investigate new organic and organometallic reactions and use these processes to synthesize biologically active compounds.

Jeffery Kelly and his group are exploring the interface between chemistry, biology, and medicine. Their projects aim to understand the physical and biological basis of protein folding, and the misfolding and aggregation processes leading to age-onset neurodegenerative diseases. Comprehension of the latter processes is used to develop new small-molecule therapeutic strategies for a variety of neurodegenerative diseases.

Anita Wentworth and her group are investigating the chemical basis of complex disease states and are synthesizing peptide and small molecule–based therapeutics. Their research is focused on disease states that have a prominent inflammatory and reactive oxygen-species chemical component, such as atherosclerosis, Alzheimer's disease, and other diseases of aging.

Researchers in Floyd Romesberg’s laboratory are using diverse techniques ranging from bioorganic and biophysical chemistry to bacterial and yeast genetics to understand and manipulate the process of evolution. Major efforts include designing 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 recently developed extremely concise chemical solutions to the synthetic challenges posed by numerous marine natural product families, including sceptrin, ageliferin, chartelline, haouamine, welwitindolinones, and the stephacidins. These syntheses are characterized by striking brevity, new biosynthetic postulates, the invention of a new methodology, and a minimum use or complete absence of protecting groups and superfluous oxidation-state manipulations.

The Frontiers in Chemistry Lecturers (17th Annual Symposium) for the 2005–2006 academic year were Richard Lerner, Scripps Research; Peter Vollhardt, University of California, Berkeley; Dieter Enders, Institute of Organic Chemistry, RWTH Aachen, Germany; and K.C. Nicolaou, Scripps Research. Thomas Scanlan (University of California, San Francisco) also visited Scripps this year as the Novartis Lecturer in Organic Chemistry, 2005.