Ralph F. Hirschmann Award In Peptide Chemistry

By developing and applying truly breakthrough scientific methodologies, Stephen J. Benkovic has had a profound impact on understanding protein-protein interactions and how proteins function as catalysts. His colleagues describe him as a true world leader in the field of chemical biology.

Benkovic, 71, has been recognized for many major advances in his career, including discovering the kinetic basis for the high fidelity of the polymerase enzymes responsible for DNA replication, working out the assembly and function of the T4 phage replisome, figuring out the anomeric specificity of the enzymes responsible for glycolysis and gluconeogenesis, and describing the kinetic turnover cycle for dihydrofolate reductase.

One of Benkovic’s signature accomplishments is his pioneering method for discovering small-molecule modulators that are biologically synthesized in cells that can interrupt or augment protein-protein interactions. Called split intein-mediated circular ligation of peptides and proteins, the technology can produce a large specific library of intracellular peptide compounds that can be used to study a variety of cellular targets.

“Biologically synthesized libraries of small molecules can be several-fold larger and allow straightforward identification of the active member,” compared with other chemical library methods, Benkovic says.

The Benkovic group has used this process to find protein-protein interaction inhibitors for enzymes involved in de novo purine biosynthesis—an important pathway for cancer cells that depend more heavily on new synthesis than on salvage. Benkovic’s group discovered that cyclic peptides were at least an order of magnitude more potent than linear peptides in inhibiting enzyme activity for this synthesis.

Because of his expertise, Benkovic has been courted by industry. He has headed the scientific advisory board of GlaxoSmithKline and participated in key decisions on the company’s drug portfolio and its entry in human genomics. He has also served on many biotechnology company boards and, together with Lucy Shapiro of the Stanford School of Medicine, founded Anacor, a biotech company focused on discovery of novel anti­bac­ter­ial and antifungal agents.

Benkovic has also been highly honored by his peers. He was elected to both the National Academy of Sciences and the Institute of Medicine and is a member of the American Academy of Arts & Sciences. His many awards include the American Chemical Society Nakanishi Prize, the ACS Alfred Bader Award in Bioinorganic or Bioorganic Chemistry, the Christian B. Anfinson Award in Protein Chemistry, the Pfizer Award in Enzyme Chemistry, the Repligen Award, and the Benjamin Franklin Medal in Life Sciences. He has also received numerous fellowships and lectureships over his distinguished career.

Although most of Benkovic’s research career has been at Pennsylvania State University, he received undergraduate degrees in both chemistry and English literature from Lehigh University. “As a senior undergraduate chemistry major, I was introduced to the subject of biochemistry,” Benkovic tells C&EN. “Although at the time it was mainly catabolic and metabolic cycles to memorize, I knew then there were many challenging problems at the chemistry/biology interface that would be fascinating to explore.”

Benkovic went on to receive a Ph.D. in organic chemistry from Cornell University. He started his academic career at Penn State in 1965 and is presently the Evan Pugh Professor of Chemistry and holds the Eberly Chair in Chemistry.

Benkovic will present the award address before the Division of Biological Chemistry.