University of Utah REU

University of

Utah URE BY ALEX GUZMAN

During the summer of 2019, I had the opportunity to conduct organic chemistry research at the University of Utah in Salt Lake City through the university’s Research Experiences for Undergraduates (REU) program. Funded by the National Science Foundation, REU programs at universities nationwide provide students with the resources to conduct cutting-edge research and attend professional and academic development events. Additionally, REU programs often organize social events aimed at fostering a fun and inclusive cohort. Most programs offer an attractive stipend and university housing for the 10-week research period, allowing REU participants to engage in their research and enjoy what the local region has to offer.

I had been considering attending graduate school for chemistry since my sophomore year, but I was unsure whether it was the right fit for me. By conducting summer research at the University of Puget Sound in the laboratory of Professor Luc Boisvert, I became accustomed to how a research laboratory operates, and I gained a genuine interest in pursuing more research. Nevertheless, I still felt the need to immerse myself in a graduate research setting before I decided whether I would apply to graduate school. I found the opportunities provided by REU programs appealing because I could gain first-hand insight into the graduate research world. I learned more about the various REU programs by exploring the REU websites. To better refine my search, I specifically searched for programs at universities that have notable organic chemistry or sustainable chemistry research. Location was also a factor that helped me determine which programs to apply for. The University of Utah gave me the opportunity to explore the stunningly beautiful state and experience a region of the United States that was previously unfamiliar to me.

The University of Utah is well known for its exceptional medical school and bioscience research. Consequently, there are many faculty members in the Department of Chemistry conducting interdisciplinary studies to solve some of the greatest challenges currently facing the medical field. Professor Andrew G. Roberts, my REU project advisor, investigates synthetic peptide chemistry with the aim of achieving more effective and far-reaching peptide-based therapeutics.

Composed of amino acid monomers (single units), peptides are polymers, which can be thought of as a chain of amino acid constituents. Each amino acid monomer has the same general chemical structure that is shown in Scheme 1. The R group in Scheme 1 represents the amino acid side chain that varies for each amino acid and defines the particular amino acid.

Scheme 1.

Peptides are fundamental to many biochemical systems and are most commonly known as the building blocks of proteins. Recently, there has been a greater interest in the medical and chemical fields to utilize peptides for their antiviral, antimicrobial, and antitumor properties (1). These therapeutic peptides are in the contemporary spotlight because they exhibit relatively low toxicity, and they bind more effectively to target proteins when compared to traditional small-molecule drugs. However, one of the great challenges for developing effective therapeutic peptide drugs is the susceptibility of peptides to metabolic degradation, which hinders the active lifespan of therapeutic peptides (2). Natural metabolic peptide degradation is carried out by proteins called proteases, which act like scissors that sever

peptide bonds (see Scheme 2). Although the problem of rapid metabolic degradation has stunted the development of effective therapeutic peptides, not all therapeutic peptides are broken down at problematic rates. Studies have shown that macrocyclic peptides, peptides with a cyclic structure consisting of 12 or more atoms, reduce metabolic degradation rates (3). Macrocyclic peptides can be synthetically achieved, but current synthetic methods face several limitations.

Scheme 2.

The most crucial, yet difficult, step in macrocyclic peptide synthesis is ring formation or peptide cyclization. Several cyclization methods introduce chemical linkers, which are not native to the peptide system (1). The introduction of non-native components may alter therapeutic effectiveness, and such methods cannot be used to achieve naturally occurring macrocyclic peptides. Furthermore, the chemistry used for several cyclization methods is not compatible with a given peptide system, meaning that the peptide’s amino acid constituents are altered during ring formation (1). Finally, there are few methods that are chemoselective. Chemoselectivity is a characteristic of chemical reactions that describes the ability to preference reaction outcomes. Therefore, in the context of peptide cyclization chemistry, low chemoselectivity translates to unpredictable and unwanted cyclization locations. The problems associated with macrocyclic peptide synthesis have produced a need to find a more general and predictable technique for peptide cyclization.

The goal of my summer REU project was to develop Scheme 3.

a macrocyclic peptide synthesis technique that is both chemoselective and widely compatible with amino acid side chains. Tryptophan (Trp) (see Scheme 1) is a commonly occurring amino acid in peptides, and it has been shown that tryptophan may undergo a chemoselective reaction with triazolinediones (TADs) (4). My project aimed to employ the Trp-TAD reactivity in the context of peptide macrocyclization, essentially using TAD as a linker for ring formation. The technique involves appending a TAD precursor to one side of a non-cyclized peptide and then reacting TAD with Trp to form a cyclic structure. The critical Trp-TAD cyclization occurs after an oxidation reaction that forms TAD and initiates the spontaneous cyclization reaction of Trp and TAD (see Scheme 3).

By the end of the summer, I had successfully synthesized the non-cyclized peptide precursor shown in Scheme 3. I tested several oxidation conditions in an attempt to form the first Trp-TAD macrocyclic peptide; however, the oxidation conditions that I tested did not form the macrocycle. Nevertheless, I am proud of the progress that I made, and I am glad to have had the opportunity to share my summer’s work at the University of Utah Summer Symposium. I am also proud to have contributed to a project that could influence the development of new therapeutic peptide medicines. Beyond the chemistry skill set I gained from my research experience, the University of Utah REU helped me determine that I am ready to pursue graduate studies and continue researching fascinating chemistry.