Skaggs Institute for Chemical Biology
Wide-angle perspective: Looking down the barrel
of the cylindrical capsule, we find n-tetradecane
in a coiled, helical conformation. At first glance,
this imposition of host on guest appears unfavorable, but in the end, adaptation maximizes
contact between the two and results in an
induced-fit match. Work for the image done by
Michael P. Schramm, Ph.D., The Skaggs Institute
for Chemical Biology.
Trevor Dale
Graduate Student, Chemistr y
The Skaggs Institute for
Chemical Biology
THE SKAGGS INSTITUTE FOR CHEMICAL BIOLOGY
THE SKAGGS INSTITUTE
FOR CHEMICAL BIOLOGY
S TA F F
Julius Rebek, Jr., Ph.D.*
Professor and Director
Carlos F. Barbas III, Ph.D.**
Professor
Janet and W. Keith Kellogg II
Chair in Molecular Biology
Tamas Bartfai, Ph.D.
Professor
Chairman, Molecular and
Integrative Neurosciences
Department, Scripps
Research
Director, Harold L. Dorris
Neurological Research
Institute
Ernest Beutler, M.D.***
Professor
Chairman, Department of
Molecular and Experimental
Medicine, Scripps Research
Dale L. Boger, Ph.D.*
Richard and Alice Cramer
Professor of Chemistry
Geoffrey Chang, Ph.D.**
Associate Professor
Benjamin F. Cravatt,
Ph.D.****
Professor
Director, Helen L. Dorris
Child & Adolescent NeuroPsychiatric Disorder
Institute
Philip Dawson, Ph.D.*****
Associate Professor
Gerald M. Edelman, M.D.,
Ph.D. †
Professor
Chairman, Department of
Neurobiology, Scripps
Research
Albert Eschenmoser, Ph.D.*
Professor
Martha J. Fedor, Ph.D.**
Associate Professor
M.G. Finn, Ph.D.*
Associate Professor
Elizabeth D. Getzoff,
Professor
Ph.D.††
M. Reza Ghadiri, Ph.D.*
Professor
Kim D. Janda, Ph.D.*
Professor
Ely R. Callaway, Jr., Chair
in Chemistry
Director, The Worm Institute
for Research and Medicine
Gerald F. Joyce, M.D.,
Ph.D. †††
Professor
Dean, Faculty
Ehud Keinan, Ph.D.**
Adjunct Professor
Jeffery W. Kelly, Ph.D.*
Lita Annenberg Hazen
Professor of Chemistry
Dean, Graduate and
Postgraduate Studies
Richard A. Lerner, M.D. †††
President, Scripps Research
Lita Annenberg Hazen
Professor of
Immunochemistry
Cecil H. and Ida M. Green
Chair in Chemistry
Stephen P. Mayfield,
Ph.D.*****
Professor
Associate Dean, Kellogg
School of Science and
Technology
K.C. Nicolaou, Ph.D.*
Aline W. and L.S. Skaggs
Professor of Chemical Biology
Darlene Shiley Chair in
Chemistry
Chairman, Department of
Chemistry, Scripps Research
Paul R. Schimmel, Ph.D. †††
Ernest and Jean Hahn
Professor and Chair in
Molecular Biology and
Chemistry
2006
THE SCRIPPS RESEARCH INSTITUTE
Peter Schultz, Ph.D.*
Professor
Scripps Family Chair
11
Lionel Moisan, Ph.D.
Andrew Myles, Ph.D.
Severin Odermatt, Ph.D.
K. Barry Sharpless, Ph.D.*
W.M. Keck Professor of
Chemistry
Subhash C. Sinha, Ph.D.**
Associate Professor
John A. Tainer, Ph.D.**
Professor
James R. Williamson, Ph.D.†††
Professor
Associate Dean, Kellogg
School of Science and
Technology
Ian A. Wilson, D.Phil.**
Professor
Chi-Huey Wong, Ph.D.*
Ernest W. Hahn Professor
and Chair in Chemistry
Riccardo Salvio, Ph.D.
Michael Schramm, Ph.D.
Siddhartha Shenoy, Ph.D.
Alessandro Volonterio, Ph.D.
Felix Zelder, Ph.D.
* Joint appointment in the
Department of Chemistry
** Joint appointment in the
Department of Molecular Biology
*** Joint appointment in the
Department of Molecular and
Experimental Medicine
**** Joint appointments in the
Departments of Cell Biology and
Chemistry
***** Joint appointment in the
Department of Cell Biology
†
Peter E. Wright, Ph.D.**
Professor
Cecil H. and Ida M. Green
Investigator in Biomedical
Research
Chairman, Department of
Molecular Biology, Scripps
Research
Kurt Wüthrich, Ph.D. †††
Cecil H. and Ida M. Green
Professor of Structural
Biology
RESEARCH
A S S O C I AT E S ††††
Dariush Ajami, Ph.D.
Elizabeth Barrett, Ph.D.
Sara Butterfield, Ph.D.
Alexandre Carella, Ph.D.
Naran Gombosuren, Ph.D.
Clemens Haas, Ph.D.
Junli Hou, Ph.D.
Richard J. Hooley, Ph.D.
Tetsuo Iwasawa, Ph.D.
Enrique Mann, Ph.D.
††
†††
††††
Joint appointment in the
Department of Neurobiology
Joint appointments in the
Departments of Molecular
Biology and Immunology
Joint appointments in the
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.
THE SKAGGS INSTITUTE FOR CHEMICAL BIOLOGY
In 1996, The Scripps Research Institute established The Skaggs Institute for Chemical Biology, made possible by a gift of more than $100 million to The Skaggs Institute for Research from Aline W. and L.S. Skaggs.
Scientific members of the Skaggs Institute hold dual appointments in various departments at Scripps
Research. These scientists have broad expertise in areas including the structure of biological macromolecules, chemical and antibody catalysis, synthetic and combinatorial chemistry, molecular recognition, and
molecular modeling methods. With the achievements of its staff, the Skaggs Institute has assumed its
research identity in the United States and throughout the world at the interface of biology and chemistry.
THE SKAGGS INSTITUTE FOR CHEMICAL BIOLOGY
Julius Rebek, Jr., Ph.D.
Director’s Overview
he Skaggs Institute for Chemical Biology, established in 1996, is now completing its 1st decade.
During this time, the generous endowment of the
Skaggs family has supported the research of more than
30 principal investigators and some 500 postdoctoral
fellows and graduate students. These researchers have
produced more than 2,000 publications in the areas of
chemistry, chemical biology, molecular biology, and
immunology gaining the Skaggs Institute a worldwide
reputation for excellence. Highlights of some of the
research done this past year are discussed briefly below,
and the individual reports of the principal investigators
are presented elsewhere in this volume.
Researchers in the laboratories of Geoffrey Chang
and M.G. Finn have taken multidisciplinary measures to
design inhibitors to biological molecules that cause cancer drug resistance. These measures take advantage of
x-ray structures of drug “antiporters” and electron cryomicroscopy to study changes in the shapes of the molecules as they perform.
Stephen Mayfield’s group is using algae as a system for production of therapeutic proteins. Specifically,
they have developed a human anti-anthrax antibody by
using samples obtained from soldiers who had been vac-
T
2006
THE SCRIPPS RESEARCH INSTITUTE
13
cinated against anthrax. Other antibodies are targeted
as anticancer agents, particularly those related to childhood lymphomas. Chi-Huey Wong and his group are
using enzymes as reagents for organic synthesis; an
ultimate target is to use these enzymes to modify proteins with sugars on their surfaces, leading to the development of vaccines against HIV, influenza, and breast
cancer. This approach is complemented by a new ligation method that uses a sugar derivative to accelerate
the coupling of protein fragments.
Paul Schimmel’s research continues to be centered
on the apparatus that converts genetic information into
proteins. The enzymes that attach amino acids to tRNA
were discovered to have an additional activity as cellsignaling proteins. These cytokines are needed for control
of blood vessel growth and inflammation; controlling
these signaling activities may eventually lead to therapies. Peter Wright, chairman of the Department of
Molecular Biology, is studying protein-protein and protein–nucleic acid interactions in solution. Specific targets include the transcriptional coactivators that have
been implicated in human diseases such as leukemia,
cancer, and mental retardation. Dale Boger and his group
are studying small-molecule nucleic acid binding agents;
they have synthesized naturally occurring antitumor
agents and have showed that the natural compound
and its mirror image are equally effective at covalent
binding to nucleic acids. Dr. Boger’s group is also working
on redesigning the vancomycin antibiotic to overcome
resistance. This exercise in molecular recognition has
led to a new structure that is 100-fold more effective at
binding to resistance peptides. Carlos Barbas and members of his laboratory are developing strategies to produce
antibodies that officially form or break carbon-carbon
bonds for use in organic synthesis. These antibodies
are developed by using novel recombinant strategies.
Dr. Barbas is also spearheading an effort to use small
organic molecules that show enzyme-like activities for
organic synthesis.
Ernest Beutler, chairman of the Department of Molecular and Experimental Medicine, is studying mechanisms
involved in the checkpoints that maintain genome stability. These are principle defense mechanisms against
malignant phenotypes and forces for tumor growth.
Elizabeth Getzoff characterizes the mechanisms of lightinduced protein activities, particularly in the cryptochrome
flavoproteins that are components of the circadian clocks
in animals and humans. Jamie Williamson’s group is
using nuclear magnetic resonance to study very large
14 THE SKAGGS INSTITUTE FOR CHEMICAL BIOLOGY
molecules such as viral capsid proteins in solution. The
nuclear magnetic resonance spectra reveal protein segments that are sufficiently mobile so as not to be observable by using x-ray or electron microscopy. Ian Wilson
also pursues the crystallographic characterization of
influenza virus glycoproteins. Dr. Wilson and his group
intend to improve the potency of antiviral drugs by
solving the structure of the neuraminidase and the viral
coat protein involved in the 1918 influenza pandemic.
K.C. Nicolaou, chairman of the Department of Chemistry, has made great progress in the synthesis of several
biologically active molecules. These include a number
of antitumor agents from the cytoskyrin family, murinederived antibiotics, and marinomycins. K. Barry Sharpless
and Valery Fokin continue to develop “click chemistry,”
extremely versatile reactions that drive spontaneous,
selective, and irreversible linkages between molecular
building blocks. They and their researchers are using
these reactions as a means for rapid exploration of chemical space. President Richard Lerner and Subhash Sinha
are developing antibodies for selective chemotherapy.
These involve drug conjugates and prodrugs that target
cell-surface receptors and prostate-specific membrane
antigen. The antibodies convert prodrugs into active
molecules at the sites where they are most needed.
Kim Janda’s group is exploring applications of botox in
the treatment of multiple sclerosis, stroke, and migraine.
Molecules that activate the toxin could ultimately allow
lower doses of the agent to be effective and could reduce
the immune response in these applications. Tamas Bartfai,
chairman of the Molecular and Integrative Neuroscience
Department, continues his studies on the temperature
regulation of mammals. Dr. Bartfai and his group have
used transgenic methods to develop an animal model,
“the cool mouse,” whose thermo set has been effectively lowered, resulting in reduced energy expenditure
and a longer lifetime for the animal.
Jeffery Kelly, dean of the Graduate Program, is
studying the protein folding and misfolding involved in
Alzheimer’s, Parkinson’s, and Gaucher’s diseases. They
have found that oxidative cholesterol metabolites can
modify amyloid peptide and accelerate the precipitation
associated with Alzheimer ’s disease. My own group
continues the study of molecules in extremely small
spaces, and how they interact when confined to close
range. This has led to newly discovered stereochemical
properties and a spring-loaded device for nanomachinery.
All of us are thrilled to be associated with The Skaggs
Institute for Research and are grateful for the research
2006
THE SCRIPPS RESEARCH INSTITUTE
opportunities provided by the Skaggs family’s support.
We look forward to our second decade.
THE SKAGGS INSTITUTE FOR CHEMICAL BIOLOGY
2006
INVESTIGATOR’ S REPORT
resembles that of an α-helical protein. We have built
small libraries of these compounds that target a number of protein-protein interactions implicated in, for
example, prolonged cancer states, chronic neuropathic
pain, and epilepsy.
Convex and Concave
Recognition Surfaces
J. Rebek, Jr., D. Ajami, E. Barrett, S. Biros, S. Butterfield,
A. Carella, T.J. Dale, N. Gombosuren, C. Haas, R.J. Hooley,
T. Iwasawa, E. Mann, L. Moisan, A. Myles, B. Purse,
R. Salvio, M. Schramm, H. Van Anda, A. Volonterio, F. Zelder
MIMETICS OF α-HELICES
rotein-protein interactions are involved in the regulation of a wide variety of biological processes.
These recognition events often occur between a
large protein containing a well-defined binding site and
a smaller protein with features complementary to the
site. This relationship has been compared with that of a
lock and its key: only a key with the correct grooves and
notches will fit and elicit a response. Regulation of these
events by small, synthetic molecules is a challenging but
desirable goal in medicinal chemistry. Structures that can
selectively enhance or antagonize protein-protein interactions have much promise as pharmaceuticals.
We have constructed a series of molecules that target protein-protein interactions in which the smaller
protein adopts an α-helical conformation (Fig. 1). The
P
F i g . 1 . Left, Line structure and skeletal model of a synthetic,
scaffold-based α-helix mimetic. Right, Overlay of the scaffold (light
gray) with an α-helical peptide (black tube); the side-chain functional groups used to recognize other proteins are shown as spheres.
synthesis of these molecules is modular and readily
amenable to combinatorial techniques. These structures act as scaffolds to project functional groups (the
“grooves” and “notches”) in a manner that closely
THE SCRIPPS RESEARCH INSTITUTE
15
C AV I TA N D S A S R E C E P T O R S
Cavitands are concave hosts that bind small molecules of complementary size, shape, and chemical surface. Deepened cavitands enclose most of a small guest,
but the open end reduces the selectivity and exposes
part of the guest to the external medium. Exquisite
selectivities can be achieved by using capsules that
completely surround the guest. We recently prepared a
water-soluble cavitand (Fig. 2) that coaxes hydropho-
F i g . 2 . A water-soluble synthetic receptor extracts normal alkanes and other insoluble species into aqueous solution. Inside the
cavity, the alkanes coil into a helix to maximize hydrophobic contacts with the receptor and tumble rapidly on the nuclear magnetic
resonance timescale.
bic guests into the cavity, where they are more or less
shielded from the aqueous environment. These complexes are kinetically stable; that is, exchange of guests
is slow on the nuclear magnetic resonance timescale.
The guests are surrounded by surfaces made of aromatic subunits, allowing van der Waals interactions
between host and guest. This attraction leads to conformational changes for normal hydrocarbons such as
octane; the hydrocarbons coil to make better contacts
with the inner lining of the receptor and reduce the
surfaces exposed to the aqueous environment.
A cavitand with doors that can be rotated over the
open end has been synthesized and characterized. The
doors shield guests from water and limit the size of
guests that fit the space. The increase in selectivity for
small guests allows cycloalkanes inside but excludes
longer linear counterparts of cycloalkanes. Cyclopentane
inside the cavitand is shown in Figure 3. The binding
of n-hexane causes the doors to fully open and expose
the guest to the aqueous surroundings. The closed doors
16 THE SKAGGS INSTITUTE FOR CHEMICAL BIOLOGY
2006
THE SCRIPPS RESEARCH INSTITUTE
Menozzi, E., Onagi, H., Rheingold, A.L., Rebek, J., Jr. Extended cavitands of
nanoscale dimensions. Eur. J. Org. Chem. 3633, 2005, Issue 17.
Menozzi, E., Rebek, J., Jr. Metal directed assembly of ditopic containers and
their complexes with alkylammonium salts. Chem. Commun. (Camb.) 5530,
2005, Issue 44.
Purse, B.W., Gissot, A., Rebek, J., Jr. A deep cavitand provides a structured environment for the Menschutkin reaction. J. Am. Chem. Soc. 127:11222, 2005.
Purse, B.W., Rebek, J., Jr. Functional cavitands: chemical reactivity in structured
environments. Proc. Natl. Acad. Sci. U. S. A. 102:10777, 2005.
F i g . 3 . Two views of a water-soluble cavitand with rotating doors
on its upper rim. Two doors close access to the cavity and slow the
uptake and release of guests. The guest shown is cyclopentane.
also reduce the rate of motion as various small guests
go in and out of the cavitand.
Cavitands have also been outfitted for catalysis by
introducing a metal complex fused to the upper rim.
This complex features a deep cavity for driving guest
recognition and a metal ion at the top of the cavity that
is positioned to coordinate a phosphate group of the
guest. These binding forces act simultaneously on smaller
molecules that bear phosphocholine subunits as shown
in Figure 4. Reactions that have been catalyzed involv-
F i g . 4 . Left, Line drawing of a cavitand outfitted with a salen
ligand with a zinc ion. Right, Energy-minimized structure of the complex of the cavitand and a simplified phosphocholine model (a wall
of the cavitand has been removed for viewing clarity).
ing a choline substrate include acylation, aminolysis,
and ester cleavage.
PUBLICATIONS
Haas, C.H., Biros, S.M., Rebek, J., Jr. Binding properties of cavitands in aqueous
solution: the influence of charge on guest selectivity. Chem. Commun. (Camb.)
6044, 2005, Issue 48.
Hooley, R.J., Biros, S.M., Rebek, J., Jr. A deep, water-soluble cavitand acts as a
phase-transfer catalyst for hydrophobic species. Angew. Chem. Int. Ed. 45:3517,
2006.
Hooley, R.J., Biros, S.M., Rebek, J., Jr. Normal hydrocarbons writhe and tumble
rapidly in a deep, water-soluble cavitand. Chem. Commun. (Camb.) 509, 2006,
Issue 5.
Hooley, R.J., Rebek, J., Jr. Deep cavitands provide organized solvation of reactions. J. Am. Chem. Soc. 27:11904, 2005.
Hooley, R.J., Van Anda, H.J., Rebek, J., Jr. Cavitands with revolving doors regulate binding selectivities and rates in water. J. Am. Chem. Soc. 128:3894, 2006.
Zelder, F.H., Rebek, J., Jr. Cavitand templated catalysis of acetylcholine. Chem.
Commun. (Camb.) 753, 2006, Issue 7.
Zelder, F.H., Salvio, R., Rebek, J., Jr. A synthetic receptor for phosphocholine
esters. Chem. Commun. (Camb.) 1280, 2006, Issue 12.