Harran group awarded NSF grant to study small molecule protein mimics

By Penny Jennings

This article was originally published by UCLA Chemistry & Biochemistry

Professor Patrick Harran, UCLA’s Donald J. and Jane M. Cram Professor of Organic Chemistry, and his group have been awarded a grant by National Science Foundation (NSF) Division of Chemistry to study fluorinated peptidomimetics. Research groups around the world are pursuing cyclic peptides and peptidomimetics as probes for biology research and leads for drug discovery. The composite macrocycles being explored by Harran are new structural types that address perennial challenges in the field.

Dr. Salvador Bernardino, Angel Mendoza and Morris Dweck

Accordingly, insulin that remains stable for longer without refrigeration could reduce the drug’s cost by making logistics less expensive. And an extended shelf life would cut back on both wasted medicine and potentially dangerous situations where expired insulin delivers an inadequate dose. More than that, insulin could become accessible to some remote locales that are currently out of reach for refrigerated transport.

A series of studies led by Maynard over the last three years has demonstrated pTrMA’s potential. A recent Innovation Fund–supported study published in ACS Applied Materials & Interfaces found that the polymer preserved insulin at temperatures of nearly 200 degrees Fahrenheit — close to water’s boiling point — and through almost a year of refrigerated storage, with 87% of the medication remaining intact, compared with less than 8% of insulin alone. Laboratory experiments into pTrMA’s safety showed that it did not trigger an immune response in mice.

Studies by former graduate student Dr. Salvador Bernardino (Ph.D. ’22 Organic Chemistry, currently research scientist at Eli Lilly), NSF pre-doctoral fellow Angel Mendoza and graduate student Morris Dweck, made the proposal possible. Using perfluorocycloalkenes, they discovered new reaction cascades that convert linear peptides into polycyclic derivatives with remarkable architectures. Their programmable chemistry occurs at room temperature in the absence of catalysts or heavy metals. Reaction products adopt conformations that mimic an array of loop structures displayed at protein surfaces. Importantly, numerous of their compounds are passively membrane permeant. Early results have been published (Angew. Chem. Intl. Ed. (2020) 59, 674-678) and a second manuscript is currently under review. The long-term goal to is translate initial findings into a general platform for creating stable, soluble mimics of intracellular regulatory proteins.

Harran received his bachelor’s degree from Skidmore College in New York. He obtained a Ph.D. from Yale University in 1995 and completed an NIH-sponsored postdoctoral fellowship at Stanford University in 1997. That fall, he joined the faculty at the University of Texas Southwestern Medical Center. In 2005, he was promoted to Full Professor and named the Mar Nell & F. Andrew Bell Distinguished Chair in Biochemistry. He joined the faculty at UCLA in July 2008 as the inaugural D.J. & J.M. Cram Chair in Organic Chemistry. He served as Vice Chair of Graduate Education for the department from 2016 to 2022. In July 2023, he will become director of the UCLA/NIH CBI training program.