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THE SKAGGS INSTITUTE FOR CHEMICAL BIOLOGY


STAFF

Julius Rebek, Jr., Ph.D.* Director and Member
Carlos F. Barbas III, Ph.D.** Associate Member
Ernest Beutler, M.D.,*** Member
Dale L. Boger, Ph.D.* Member, Richard and Alice Cramer Professor
Benjamin F. Cravatt, Ph.D.**** Assistant Member
Philip Dawson, Ph.D.**** Assistant Member
Gerald M. Edelman, M.D., Ph.D.***** Member
Albert Eschenmoser, Ph.D.* Member
Martha J. Fedor, Ph.D.** Associate Member
Elizabeth D. Getzoff, Ph.D.** Associate Member
M. Reza Ghadiri, Ph.D.* Associate Member
Donald M. Hilvert, Ph.D.* Member, Janet and Keith Kellogg Professor
Kim D. Janda, Ph.D.+ Member, Ely R. Callaway, Jr., Chair
Gerald F. Joyce, M.D., Ph.D.+ Associate Member
Ehud Keinan, Ph.D.** Adjunct Member
Jeffery W. Kelly, Ph.D.* Member
Richard A. Lerner, M.D.+ Member, President and CEO, Lita Annenberg Hazen Professor, Cecil H. and Ida M. Green Chair
Stephen P. Mayfield, Ph.D.**** Associate Member
K.C. Nicolaou, Ph.D.* Member, Aline W. and L.S. Skaggs Professor, Darlene Shiley Chair
Paul R. Schimmel, Ph.D.** Member
K. Barry Sharpless, Ph.D.* Member
W.M. Keck Professor
Erik J. Sorensen, Ph.D.* Assistant Member
John A. Tainer, Ph.D.** Member
James R. Williamson, Ph.D.** Member
Ian A. Wilson, D.Phil.** Member
Chi-Huey Wong, Ph.D.* Member, Ernest W. Hahn Professor and Chair
Peter E. Wright, Ph.D.** Member, Cecil H. and Ida M. Green Investigator in Medical Research


RESEARCH ASSOCIATES++

Christoph Boss, Ph.D.
Thomas Heinz, Ph.D.
Göran Hilmersson, Ph.D.
Carina Horn, Ph.D.
Byeang Hyean Kim, Ph.D.
Arne Luetzen, Ph.D.
Shihong Ma, Ph.D.
Tomas Martin, Ph.D.
Sandro Mecozzi, Ph.D.
Daniel Mink, Ph.D.
Derek Nelson, Ph.D.
Ulrike Obst, Ph.D.
Doris Pupowicz, Ph.D.
Christian Rojas, Ph.D.
Dmitry Rudkevich, Ph.D.
Javier Santamaria, Ph.D.
Tomas Szabo, Ph.D.
Yuji Tokunaga, Ph.D.
Boris Vauzeilles, Ph.D.
Siegfried Waldvogel, Ph.D.
Sabine Wallbaum, Ph.D.


* Joint appointment in Department of Chemistry
** Joint appointment in Department of Molecular Biology
*** Joint appointment in Department of Molecular and Experimental Medicine
**** Joint appointment in Department of Cell Biology
***** Joint appointment in Department of Neurobiology
+ Joint appointments in Departments of Chemistry and Molecular Biology
++ Research Associates in the laboratories of staff other than Dr. Rebek are included in the lists of the respective departments in which the associates hold joint appointments.


With the exception of the Director's report, reports of all other investigators who hold joint appointments in The Skaggs Institute for Chemical Biology are located in the sections for the investigators' respective departments. The information is also highlighted in a separate special report on The Skaggs Institute.
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Director's Overview

Julius Rebek, Jr., Ph.D.

The Skaggs Institute for Chemical Biology has now completed its second full year and, thanks to the extraordinary munificence of Aline and Sam Skaggs, is fully funded. The Institute consists of more than 20 principal investigators in six departments, including Chemistry, Molecular Biology, Cell Biology, Neurobiology, and Molecular and Experimental Medicine. The Institute also has a physical presence in the building formerly known as Molecular Biology. The researchers have broad expertise in determining the structure of biological macromolecules, devising chemical and antibody catalysts, synthesizing natural products and combinatorial libraries, effecting molecular recognition, and designing methods for molecular modeling. These programs give the Institute its research identity at the interface of chemistry and biology in the United States and worldwide.

The reports in this publication highlight the individual achievements of the principal investigators. These accomplishments include the determination of the crystal structure of the T-cell receptor, the synthesis of antitumor agents, the discovery of multipurpose antibodies, the characterization of lipidlike hormones, the regulation of cell adhesion molecules, and the invention of self-replicating peptides. A more subtle accomplishment is the synergy that the Skaggs Institute has made possible between research groups.

For example, an initiative in RNA chemistry and biology is emerging around the recent recruitment of Paul Schimmel, Martha Fedor, and James Williamson. Their intent is to develop an understanding of the structure and function of these key molecules of life that will ultimately lead to new therapeutic agents. As another example, four groups now work in molecular evolution, research related to the origins of life. The depth of this effort has made the Skaggs Institute the leading edge for research in this field. A third cohesive effort is in drug design, which brings the Institute's superb structural and computational facilities for proteins and nucleic acids together with the expertise in organic synthesis and combinatorial chemistry.

The capability of the Skaggs Institute to assume broad, long-term projects makes it unique, and as we enter our third year, we are eyeing strategic opportunities in newly emerging fields that blend chemistry with biology. Nowhere does this seem more likely than in the opportunities expected to emerge from the sequencing of the genomes of living organisms and from the conversion of biological information pouring out of such projects to a science at the molecular level. This conversion will involve determining the genes that encode the specific proteins, receptors, or nucleic acids associated with a particular state; unraveling the interactions of those genes; and ultimately controlling the interactions by means of appropriate synthetic agents. Because an enormous array of small molecules is already available (and more agents will become available) through combinatorial chemical synthesis, it seems inevitable that the disciplines of genomics and combinatorial chemistry will meet at the biological macromolecules--the therapeutic targets--of the disease.

We intend to maintain the Skaggs Institute as the model for research in chemical biology and to provide a nurturing environment for the next generation of scientists. Accordingly, we will continue to recruit and maintain the very best researchers, even if their scientific interests do not fall neatly into one of the existing research efforts. The ultimate research identity of the Skaggs Institute will be the scientists it produces.

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Investigator's Report


Intermolecular Forces and Interactions

J. Rebek, Jr., C. Boss, C.G. Hilmersson, C. Horn, B.-H. Kim, T. Martin, S. Mecozzi, D. Mink, D. Nelson, U. Obst, C. Rojas, D. Rudkevich, J. Santamaria, T. Szabo, Y. Tokunaga, B. Vauzeilles, S. Waldvogel, S. Wallbaum

SK1.gif SELF-ASSEMBLY

Being complementary and self-complementary is the universal feature of self-assembling systems. In Nature, multiple copies of a single entity, such as a viral coat protein or an allosteric enzyme, give rise to superstructures with functions that emerge only in the assembled state. We have been exploring small, completely synthetic molecules that also have these properties. In particular, we have been able to generate capsule structures, closed-shell surfaces that can encapsulate smaller molecules (Fig. 1). With these structures, we have seen how release of solvent can drive encapsulation, how more than one molecule can be encapsulated, how the concentrations of an encapsulated species resemble the concentrations in the liquid state, and how accelerations in the rate of bimolecular reactions can be observed inside the capsule. Control of the uptake and release of encapsulated small molecules is the current goal.
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MOLECULAR DIVERSITY AND COMBINATORIAL CHEMISTRY

One of the most rapidly developing areas in the chemical sciences is molecular diversity. In bioorganic chemistry, the research centers on the development of synthetic combinatorial libraries.
Recent innovations, many from the Department of Chemistry, make use of solution-phase approaches in addition to solid-phase synthesis more attractive. We have developed methods of synthesizing and analyzing tetraurea-based libraries. The urea function is more biologically available and stable than is the secondary amide (peptide) bond, and we have generated several libraries of more than 2000 molecules, each with a xanthene skeleton (Fig. 2). A screening protocol (deconvolution) was used to detect and characterize molecules that inhibit binding of transcription factors to DNA. These molecules show activity toward DNA as intercalators.
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STUDIES IN MOLECULAR RECOGNITION

How molecules fit together is often determined by their surface shapes and how well the molecules fill space. Many biologically interesting macromolecule targets present a concave surface to their small-molecule substrates and messengers. We are exploring these complementary relationships with synthetic structures that have large concave surfaces and functional groups that are directed inward. Figure 3 shows such a scaffold in which the carboxylic function is directed at an asymmetric microenvironment. These concave molecules can be used to distinguish between small molecules and mirror images of the small molecules and can also be used to measure the strength of hydrogen bonds.
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CATALYSIS AND AUTOCATALYSIS

Molecules that self-assemble and are self-complementary are also prime candidates for acting as templates for their own construction (Fig. 4). We have observed autocatalysis during the formation of some unusual receptors, in which recognition at one end of the molecule positions reactive functionalities at another end that accelerate the reaction. The product is an exact copy of the template. These systems may represent a new generation of self-replicating molecules that show function.
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SMART POLYMERS

We have devised a new kind of capsule in which the two pieces are attached to each other in such a way that they must assemble in polymeric form. These polymeric capsules or "polycaps" can bind simple organic and bioorganic molecules such as camphor in a reversible fashion and allow uptake and release of the molecules on timescales that range from seconds to hours (Fig. 5). A second generation of these systems that involves three components leads to a highly cross-linked structure that is also formed reversibly. We are exploring the applications of polycaps in slow-release devices for delivery of small organic structures and as sensors.

PUBLICATIONS

Boumendjel, A., Roberts, J., Hu, E., Pallai, P., Rebek, J., Jr. Design and asymmetric synthesis of ß-strand peptidomimetics. J. Org. Chem. 61:4434, 1996.

Castellano, R., Rudkevich, D., Rebek, J., Jr. Tetramethoxy calix[4]arenes revisited: Conformational control through self-assembly. J. Am. Chem. Soc. 118:10002, 1996.

Castellano, R.K., Rudkevich, D.M., Rebek, J., Jr. Polycaps: Reversibly formed polymeric capsules. Proc. Natl. Acad. Sci. U.S.A., in press.

Conn, M.M., Rebek, J., Jr. Self-assembling capsules. Chem. Rev., in press.

Kang, J., Rebek, J., Jr. Acceleration of a Diels-Alder reaction by a self-assembled molecular capsule. Nature 385:50, 1997.

Kang, J., Rebek, J., Jr. Entropically-driven binding in a self-assembling molecular capsule. Nature 382:239, 1996.

Kato, Y., Toledo, L.M., Rebek, J., Jr. Energetics of a low barrier hydrogen bond in nonpolar solvents. J. Am. Chem. Soc. 118:8575, 1996.

Meissner, R., Garcias, X., Mecozzi, S., Rebek, J., Jr. Synthesis and assembly of new molecular hosts: Solvation and the energetics of encapsulation. J. Am. Chem. Soc. 119:77, 1997.

Rebek, J., Jr. Assembly and encapsulation with self-complementary molecules. Chem. Soc. Rev., 1996, p. 255.

Rebek, J., Jr. Molecular assembly and encapsulation. Pure Appl. Chem. 68:1261, 1996.

Rojas, C., Rebek, J., Jr. Functional groups positioned in unusual asymmetric microenvironments. Bioorg. Med. Chem. Lett. 6:3013, 1996.

Rudkevich, D.M., Rebek, J., Jr. Chemical selection and self-assembly in a cyclization reaction. Angew. Chem. Int. Ed. Engl. 36:846, 1997.

Shipps, G.W., Pryor, K.E., Xian, J., Skyler, D.A., Davidson, E.H., Rebek, J., Jr. Synthesis and screening of small molecule libraries active in binding to DNA. Proc. Natl. Acad. Sci. U.S.A., in press.

Valdés, C., Toledo, L., Spitz, U., Rebek, J., Jr. Structure and selectivity of a small dimeric encapsulating assembly. Chem. Eur. J. 2:989, 1996.

Wintner, E.A., Rebek, J., Jr. Combinatorial libraries in solution: Polyfunctionalized core molecules. In: Combinatorial Chemistry Synthesis and Application. Wilson, S.R., Czarnik, A.W. (Eds.). Wiley, New York, 1997, p. 95.

Wintner, E.A., Rebek, J., Jr. Recent developments in the design of self-replicating systems. In: Supramolecular Control of Structure and Reactivity. Hamilton, A.D. (Ed.). Wiley, New York, 1996, p. 225. Top of Page

 

 







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