Catalyzation of chemical reactions by antibodies
Schultz' group first reported the observation
(simultaneously with Richard Lerner and his coworkers) that antibodies
could selectively catalyze chemical reactions in 1986. Since those first
experiments, antibodies have been developed that catalyze a wide array of chemical
and biological reactions from acyl transfer to redox reactions. The specificities
of these catalytic antibodies rival or exceed those of enzymes and in a number of
cases rate accelerations comparable to those of enzymes have been achieved.
Moreover, catalytic antibodies have been generated for reactions not found
in enzymology and for reactions difficult to achieve via any known chemical
approaches. Because antibodies can be generated that bind to virtually any
molecule with high affinity and specificity, the field of catalytic antibodies
offers a new technology for generating tailormade enzymelike catalysts for
applications in chemistry, biology and medicine. Moreover, the characterization
of these catalytic antibodies is defining the importance of transition state
stabilization, proximity effects, general acid and base catalysis, nucleophilic
catalysts and strain in biological catalysis, as well as providing insights into
the evolution of catalytic function in nature. This field has opened new horizons
of scientific and industrial opportunities that bridge enzymology, immunology,
chemistry and medicine.
Schultz and Lerner's demonstration that the vast library of antibody molecules of the immune
system can be tapped to generate selective catalysts has also ushered in a whole new age in
chemistry in which the power of biological and chemical diversity systems (molecular libraries)
are being exploited to control reactivity and interactions of molecules. In his own lab Schultz
has applied this combinatorial approach to many problems including (1) the generation of
sequence specific DNA binding proteins, peptides and oligonucleotides (for specific applications
in gene targeting and mapping), (2) the isolation of RNA molecules that catalyze novel reactions
(expanding the scope of RNA catalysis to reactions not involving nucleic acids), (3) the
generation of whole new classes of "unnatural" biopolymers (including
oligourethanes,
oligosulfones and oligoureas) in an effort to find polymeric backbones for drug discovery
with improved pharmacological properties relative to peptides (an advance that would significantly
impact the drug discovery process - efforts are also ongoing to generate folded polymeric
structures using these unnatural backbones), and (4) libraries of purine analogues to generate
selective inhibitors of the cell cycle kinase CDK2. Schultz was a founding scientist of
Affymax Research Institute, one of the first biotechnology companies to pursue the generation
and screening of large libraries of molecules for drug discovery.
Most recently, Schultz is applying this combinatorial approach to materials science.
Specifically, he is developing a new technology for the parallel synthesis, processing and
screening of large libraries of solid state materials for new properties. Scanning inkjet
delivery systems, "masked" sputtering and laser ablation systems, and scanning microwave probes
have been developed to generate and screen large libraries of materials for superconducting
and magnetic properties. In fact, a library of high temperature superconductors has been
successfully generated and novel magnetoresistive materials identified using this approach.
This work may dramatically impact the rate at which new materials are discovered (an effort that
traditionally has involved a serendipitous trial and error process) by allowing scientists to
design, execute and analyze experiments 10,000 at a time versus one at a time. Recently,
Schultz has founded Symyx Technologies to develop and apply this new technology for materials
discovery. In other projects in the materials science area, Schultz recently showed that highly
localized chemical catalysis on surface atoms or molecules can be carried out using synthesizing
nanostructures containing complex architectures and interconnections. In a collaborative effort
with Paul Alivisatos, Schultz if developing strategies for generating spatially defined arrays of
nanoclusters to further explore this novel form of matter.
Schultz has also pioneered the development of a general biosynthetic method which, for the
first time, makes it possible to site-specifically incorporate unnatural amino acids with novel
steric and electronic properties into proteins. In the last year Schultz and coworkers have
effectively expanded the genetic code to include over eighty unnatural amino acids with novel
backbone and side chain structures. This methodology has recently been applied to studies of the
catalytic properties, specificity, and stability of a number of proteins by substituting amino
acids with altered pKa's and nucleophilicities, restricted conformations, altered redox and
steric properites as well as photoactivable and photocleavable amino acids. In addition, a
number of biophysical probes have been site-specifically inserted into proteins. This new
technology not only allows us for the first time to carry out detailed physical organic studies
on proteins, it may also provide a whole new generation of proteins with properties not
restricted by the naturally occurring twenty amino acids.
Schultz has also been involved in efforts aimed at redesigning enzyme specificity. His group
has demonstrated that chemical and biological mutagenesis can be used together to design new
enzymes with novel catalytic properties. Other efforts have focused on the (1) design of
selective protein cleaving agents (for application in protein mapping and protein inactivation),
(2) the development of a new approach for immunotherapy (based on "noncovalent
immunogenicity"),
(3) the design of stable alpha-helices as small as eight amino acids and (4) studies of the mechanism
of action of the anti-tuberculosis drugs, isoniazid and ethionamide.
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