Professor Adam Urbach, of the Department of Chemistry at Trinity University, is supported by the Organic and Macromolecular Chemistry Program for his research involving the design of molecules that recognize and label specific peptides in aqueous solution. Such compounds would have broad impact on fields ranging from basic biochemistry to medical diagnostics and therapeutics. Current approaches are synthetically challenging and thus inefficient. The PI plans to develop an approach to modifying synthetic peptide receptors that will enable rapid iteration of their design, synthesis, and characterization, thus substantially accelerating the discovery process. The teaching portion of the project focuses on incorporating undergraduate and postdoctoral students in the research, and on improving the integration of teaching and research at Trinity, with a focus on writing and experimental design skills.
The activities enabled by this grant award have produced several important and substantial outcomes that contribute to the competitiveness of the United States by providing innovations in research and an exceptional training environment that prepares students to enter the scientific and medical workforce. Fifteen undergraduate students, three technicians, and three postdocs were intimately involved in this research. One of the postdocs (Joseph Reczek) is currently a professor at Denison University. One of the technicians (Chris Schardon) is now pursuing a PhD at UT Austin. One of the undergraduate students (Lisa Heitmann Ryno) completed a PhD at the Scripps Research Institute in La Jolla and is currently a professor at Oberlin College. One (Jordan Chinai) is pursuing an MD/PhD at Albert Einstein College of Medicine. One (Nick Dybdal-Hargreaves) is pursing a DDS/PhD at UT Health Science Center at San Antonio. One (David Stuck) is pursuing a PhD in chemistry at UC Berkeley. Three (Bi Guo, Leigh Logsdon, and Jacob Reynolds) are in medical school. One (Erik Skoglund) is in pharmacy school. The others are all pursuing scientific or medical careers. These examples show the high quality of the participants and demonstrate the value of the research training as an important outcome, perhaps the most valuable societal outcome, of this grant award. The research activities have produced ten publications in top-tier journals, including 15 undergraduate coauthors, and one review article. As background: The many thousands of different types of molecules in biological systems are highly organized and work together to create larger structures and to carry out various functions. This organization occurs because the individual molecules are able to find their partners and stick together very selectively--that is, they "recognize" one another and stick only to their partners. The principal investigator's research program studies this process, known as "molecular recognition," and focuses on the design and characterization of man-made (synthetic) molecules that recognize biological molecules such as proteins and peptides by encapsulating part of their structure within the cavity of the synthetic molecule; thus, the synthetic molecules are known as receptors. Several of the publications enabled by this grant award describe new approaches to improving the interaction between synthetic receptors and polypeptides. These methods overcome classical and generally unproductive approaches by using noncovalent self-assembly to modify the properties of the receptor. One publication describes the translation of peptide recognition to protein recognition. Proteins are just large peptides, but the larger size gives them greater diversity and function. Previous approaches to peptide recognition have failed to be translated to proteins, but we showed that a synthetic receptor can bind to the protein insulin at a specific site on the protein. That site unravels from the surface of the protein and is captured by the synthetic molecule. This unusual discovery may presage a general approach to the molecular recognition of proteins, which has become a major thrust of research in the Urbach laboratory. Two of the publications describe the interfacing of synthetic receptors with proteases, which are enzymes that cut up peptides and proteins. These are powerful demonstrations of the use of synthetic receptors to rapidly characterize the activity of these enzymes and to protect peptides from being cut up by proteases. Finally, this research has produced several new materials that are useful for the separation of mixtures, including unmodified proteins.