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James S. Nowick is a professor at the University of California, Irvine (Department of Chemistry, University of California, Irvine, CA 92697-2025; 949-824-6091; jsnowick@uci.edu). He joined the faculty of UCI in 1991 as an assistant professor. His notable awards are the ACS Arthur C. Cope Scholar award (1998), the Alfred P. Sloan Research Fellowship award (1997), and the Camille Dreyfus Teacher– Scholar Award (1996). Nowick’s current research interests include bioorganic chemistry, catalysis, molecular recognition and supramolecular chemistry, peptide and protein structure, and synthetic organic chemistry. He obtained his B.S. degree from Columbia University and his Ph.D. from the Massachusetts Institute of Technology.

According to James S. Nowick, the keys to innovation are academic research, education, and outreach. Nowick joined the University of California, Irvine (UCI) faculty in 1991; he has been blazing a trail of outstanding accomplishments in research and undergraduate teaching ever since. Nowick is also the founder of the UCI Chemistry Outreach Program, which encourages students to pursue studies in chemistry by performing entertaining chemistry demonstrations at local schools in Orange County, CA.

Research

Nowick’s research program focuses on the design, synthesis, and evaluation of organic molecules that mimic the structures and interactions of proteins. The goal of his research is to develop new synthetic methods while exploring fundamentally important biological processes.

During the past few years, Nowick’s lab has developed methods for the synthesis of amino acid isocyanates, peptide isocyanates, artificial β-sheets, unnatural oligomers, and a new peptidomimetic group called Hao. All of these entities fit into the broad category of peptide and peptomimetic chemistry, and they are being used as building blocks for artificial structures that resemble proteins. Nature is adept at developing molecules that fold into functional 3-D structures, but Nowick and other researchers are only beginning to be able to develop functional molecules that fold into 3-D structures.

Nowick says that he is especially proud of the synthetic method for peptide isocyanates because these compounds have not been made before. “There was a real need for this technology. As soon as we developed it, we found people talking to us from the pharmaceutical industry who were trying to use these compounds. This new type of reactive peptides has the potential to affect a variety of people.”

Mimicking and interrupting the natural functions of biopolymers are very important goals. Once scientists achieve this, they will be able to design complex molecules that can interact with biological systems and perhaps provide some of the answers about the protein chemistry of contemporary diseases.

Figure 1. Unnatural oligomers. New synthetic methods have generated a library of unnatural oligomers that mimic polypeptides and other biopolymers. The R groups represent unspecified amino acid side chains.

Unnatural oligomers that mimic polypeptides and other biopolymers are emerging as important targets in drug discovery and other areas. Some of the representative targets include N,N-linked oligoureas, N,N´-linked oligoureas, and oligomers designed to mimic peptide β-strands. Examples of the oligomers are illustrated in Figure 1. Once Nowick’s group has developed efficient syntheses of these unnatural oligomers, they will be able to evaluate their properties using techniques such as NMR spectroscopy and X-ray crystallography and incorporate them into molecules such as those pictured in Figure 2.

Unnatural oligomers are building blocks for more complex molecules, which Nowick’s group is designing. These complex molecules have proteinlike structures and properties that mimic protein β-sheets. Nowick calls them “artificial β-sheets”. Current targets include four-stranded artificial β-sheets and an artificial β-sheets sandwich (Figure 2). The syntheses of these molecules are challenging (≥15–20

Figure 2. Artificial β-sheets. Nowick’s unnatural oligomers serve as building blocks for more complex molecules that have proteinlike structures and properties.

steps). Once the targets are synthesized, they are characterized by NMR spectroscopy and molecular modeling to determine the molecules’ structures and properties.

Developing complex molecules

Among the most interesting and important properties of unnatural oligomers and complex molecules is their ability to interact with biological systems. Nowick says, “Right now, we are particularly excited about developing molecules that can mimic and block β-sheet interactions between proteins.” These interactions are involved in protein dimerization, recognition between different proteins, and protein aggregation. Many proteins participate in these β-sheet binding interactions, including proteins associated with AIDS, Alzheimer’s disease, and cancer. Compounds that mimic β-sheets may be used to block these interactions and may ultimately lead to new drugs to treat these diseases. With these far-reaching applications in mind, Nowick’s group has begun to develop artificial β-sheets that form β-sheet dimers. By learning to control the dimerization process, they hope to develop agents that can bind to proteins through β-sheet interactions or block β-sheet formation among proteins.

Nowick’s group recently invented Hao, a new unnatural amino acid derived from hydrazine, 5-amino-2-methoxybenzoic acid, and oxalic acid groups (1). The 2,7-di-tert-butylfluorenylmethyloxycarbonyl (Fmoc*) and tert-butoxycarbonyl (Boc) protected derivatives of Hao are prepared efficiently and in high yield by condensing suitably protected derivatives of hydrazine, 5-amino-2-methoxybenzoic acid, and oxalic acid. Fmoc*–Hao and Boc–Hao behave like typical Fmoc*- and Boc-protected amino acids and can be incorporated into peptides by standard solid- and solution-phase peptide synthesis techniques using carbodiimide coupling agents. Hao-containing peptides form a β-sheetlike hydrogen-bonded dimer. Hao displays hydrogen-bonding surfaces that are complementary to the hydrogen-bonding edges of protein β-sheets

Figure 3. Hao. Molecular model of a peptide containing Nowick’s unnatural amino acid docked to the β-sheet edge of a protein. The model was drawn using Molscript (1).

(Figure 3). By understanding these β-sheet binding interactions and thus controlling the dimerization process, Nowick hopes his efforts will lead to improved drug design.

Hao is unique because it can be used in automated peptide synthesizers for rapid assembly. In the August 21 issue of Chemical & Engineering News, Nowick said, “We have readily prepared many large peptides and combinatorial libraries containing Hao and are using these compounds for structural and biological studies” (2).

Long-term research goals

The long-term goal of Nowick’s research is drug design. He says, “It would be an oversimplification to say that we are trying to design drugs with short-term goals in mind. However, we are exploring new approaches to drug design that may lead to future generations of drugs.”

When asked about industrial–academic alliances, Nowick responded, “I view academia as having the role of generating new ideas, discovering new principles, and thinking about long-term applications [a big picture approach]. Industry is very well set up for approaching problems on a short-term basis, meaning that we have 3 or 5 years to develop a new drug to treat this disease and that we need to go through an effort of discovery and evaluation and so forth.”

Obviously when there is a target disease in mind and a large population is affected, a lot of money and resources can be thrown at the problem. People with expertise are assembled to attack the problem in an assembly-line fashion. One group may be developing new molecules, another group developing biological assays, and a different group involved in the trials and so forth, all the way to marketing and process chemistry. Nowick says, “In the academic laboratory, the goal is not only to develop new reactions and compounds, but also to nurture and educate future chemists. Industry is inherently not well suited for the big picture approach.”

Bridging the science–education gap

Nowick believes that outreach is a needed, natural, and necessary extension of scientific research and undergraduate education. He believes the mission of the outreach activities is to get kids interested in chemistry, educate the public, and help educate future educators. Nowick got started in educational outreach as a graduate student at MIT in the late 1980s. He and Ron Brisbois, a fellow graduate student, decided that outreach was necessary because few opportunities were available to really inspire would-be future scientists. With this in mind, Nowick and Brisbois decided to take some of their experiences to kids at local high schools. They received a small stipend from the department of chemistry at MIT for supplies and developed a road show that included demonstrations and lectures. The original show toured 10 schools and reached 500 kids in its first year.

After this initial success, the two students decided to expand the program to get faculty and other graduate students involved. Their efforts were eventually funded by a grant from the National Science Foundation (NSF). Nowick says, “Interestingly, the people who ended up participating in the program went on to become educators either at the university, college, or high school level.”

When Nowick moved to UCI in 1991, he decided to start a similar program there. The program became known as the UCI Chemistry Outreach Program. It is supported by funding from NSF and the Dreyfuss Foundation, and it reaches about 4000 kids.

“Kids get very excited about nylon rope pulled from the interface between two solutions or liquid nitrogen freezing ice cream that can be eaten,” comments Nowick. His team invariably gets more people interested in pursuing careers in chemistry—if not the students, then definitely the outreach volunteers. Nowick says that some people who have come through the program are now undergraduates in the chemistry department at UCI and are volunteers for the outreach program.

Nowick maintains, “The primary need for outreach programs comes from so few students having a good science education. For example, most of the high school chemistry teachers don’t have graduate degrees in chemistry. Therefore, for the most part, students aren’t getting teachers who really know chemistry.”

He believes that it is more difficult to be a high school chemistry teacher than it is to be a professor of chemistry at a research university. High school teachers are not only responsible for teaching, but also have to deal with discipline problems and scarce supplies and resources. Nowick says, “Teachers are being asked to do the impossible: obtain additional certificates and take additional courses and exams, but earn for starters just a little more than half of the salary of someone with just a B.S. degree in chemistry who earns $40,000 per year. Until our leaders and our politicians are willing to invest in the future of the country and the future of the people and provide the resources, we are going to be hurting very badly.”

Undergraduate chemistry curriculum

Nowick holds a deep commitment to teaching undergraduates. In the classroom, he has developed innovative courses that bring cutting-edge organic chemistry to students. He starts his introductory organic chemistry course with an interactive molecular modeling exercise to show how chemists develop new drugs to fight AIDS. As the lesson progress, he uses these molecular modeling tools in Web-based exercises to teach stereochemistry and conformational analysis. In his advanced organic synthesis undergraduate lab course, his students perform synthetic experiments taken directly from the research literature, including an Evans asymmetric aldol reaction, a Suzuki cross-coupling reaction, and a solid-phase Ugi four-component condensation.

Nowick also involves undergraduates in his research program. Half of the more than 25 undergraduates under his tutelage are co-authors of papers in ACS journals and talks at ACS meetings, and many of these students have gone on to graduate school in chemistry.

Keys to future innovation

The interesting thing that occurs in Nowick’s program and through his academic research is that people get the chance to ask questions. In the outreach program, students get a chance to talk to the outreach volunteers and ask questions about the demonstrations, and ideas fly back and forth. This same kind of exchange occurs in academic research where the question becomes how to figure out what questions to ask.

Nowick’s take-home message is, “My research is driven by curiosity and a fundamental interest in molecular structure and interactions. Although it has been driven by questions about how molecules acquire structure, how they fold, and how to create molecules that do different things, it has rarely been driven by an overarching mandate from the beginning to focus on a particular problem. The wonderful thing about research in academia is that people can react to problems as they emerge and identify new problems by gaining expertise in a particular area.”

References

1. Nowick, J. S.; Chung, D. M.; Maitra, K.; Maitra, S.; Stigers, K. D.; Sun, Y. J. Am. Chem. Soc. 2000, 122, 7654–7661.
2. Chem. Eng. News 2000, 78 (34), 39.

Marc C. Fitzgerald is assistant editor of Chemical Innovation.