Ralph Hirschmann, the Rao Makineni Professor of Bioorganic Chemistry at the University of Pennsylvania, has made seminal contributions to organic, medicinal and bioorganic chemistry for over fifty years. A naturalized American citizen, born in Bavaria, Germany, Ralph Hirschmann came to the US in his teens and earned a B.A. degree from Oberlin College in 1943. Following three years of military service during World War II, he entered graduate school at the University of Wisconsin (Madison), where he received a Ph.D. degree under the mentorship of Professor William S. Johnson in 1950. That year he joined the Merck Research Laboratories as a process research chemist and retired in 1987, having served as Senior Vice President of Chemistry and of Basic Research. During his tenure in the latter capacity, his team discovered and/or developed several major drugs including Vasotec, Lisinopril, Primaxin, Ivomec, Mevacor and Proscar. Early in his career (1952), he discovered the steroidal C-nor-D-homo rearrangement. He explained this reaction by introducing the term “stereoelectronic control,” now an integral concept of organic chemistry. He used this concept to propose a pathway for the biosynthesis of the alkaloid jervine, the structure of which had been elucidated by Wintersteiner and Fried at Squibb. During the 1960s, with Robert G. Denkewalter, he directed the first solution total synthesis of an enzyme, ribonuclease A (RNase A), and in 1969 announced  jointly the total synthesis of ribonuclease A achieved by Merrifield on solid support. Prior to these announcements, it was questioned by many whether any synthetic protein of this size would fold correctly without a template.

     Hirschmann thrived in the interdisciplinary environment of the pharmaceutical industry. Research carried out in Rahway in the 1950s and published in the early 1960s made a significant contribution to medicinal chemistry by demonstrating that one can improve the therapeutic index of an anti-inflammatory steroid via a biochemistry-based prodrug design. Knowing that the level of N-acetyl glucosaminidase in a joint is elevated in direct relation to the severity of the disease, he generated the 21-N-acetyl glucosaminide, a biologically inactive prodrug that is selectively activated in the inflamed joint (drug latentiation). The underlying concept is widely employed now-a-days.

      Prior to his promotion to Vice President for Basic Research, in 1976, with responsibility in Rahway, West Point, Montreal and Terlings Park (UK), he served as Merck’s Executive Director of Medicinal Chemistry in West Point, Pennsylvania. Merck agreed to let the peptide group join him at West Point. There, he initiated research on the peptide hormone somatostatin that had just been isolated and characterized chemically and biologically at the Salk Institute. Diabetes-induced retinopathy was the therapeutic target. This research, directed with Daniel F. Veber, led to the elucidation of the hormone’s bioactive conformation, which has served as the basis for all subsequent chemical endeavors in the somatostatin field ever since. This research and the prior synthesis of RNase did much to stimulate peptide research in the pharmaceutical industry. Somatostatin remains one of Ralph’s principal research interests to this day.

      He started a second career at the University of Pennsylvania in 1987, where he initiated collaborative research in the field of peptidomimetics with Professors Amos B. Smith, III, and K. C. Nicolaou, now Professor of Chemistry at the Scripps Research Institute in La Jolla, CA. He also held the position of University Professor of the Medical University of South Carolina. Later collaborations were established with two other Penn colleagues, Professors David W. Christianson and Barry Cooperman, and with Professor Steven Benkovic at Pennsylvania State University. Hirschmann/Smith also collaborated with scientists at Merck (Rahway and West Point), Bristol-Meyers Squibb at Wilmington, at PanLabs, Inc., and at the Salk Institute. The collaborations with biologists in the pharmaceutical industry were critical for the success of this research. The Penn teams have published 56 papers, mostly describing new approaches to the design of peptidomimetics and (with Benkovic) of haptens for the generation of catalytic antibodies.

     Taken together the peptidomimetic research at Penn proved to be seminal. It showed that the peptide backbone is not required for receptor binding, but that the b‑D‑glucose scaffold, to which diverse substituents can be attached, can mimic b-turns; this lead ultimately to the concept of radial symmetry to explain the privileged nature of the scaffold; it also revealed (with E.R. Thornton) that analysis of aromatic electrostatic potential can correlate well with hydrophobic receptor binding and that scaffolds may contribute to receptor binding. Secondly, the collaboration established that in the design of inhibitors of proteolytic enzymes, where H-bond interactions are required, the pyrrolinone backbone offers improved transport properties over peptide bonds because of reduced solvation. It also revealed that polypyrrolinones are versatile building blocks that can generate novel helices and turns in addition to b-strands.

      Hirschmann has been recognized with three honorary degrees and three endowed lectureships; three chairs are linked to his name. He has received recognition through many awards including the Merck & Co. Inc. Board of Directors Scientific Award and the National Academy of Sciences Award for the Industrial Application of Science. He also received the Romanes Lectureship Award in Pharmacy (Edinburgh), the Agnes Borrowman Special Lectureship in Pharmacy (London University), the Nichols Medal (New York section, ACS), Chemical Pioneer Award (American Institute of Chemists), the Microbial Chemistry Medal (Kitasato University, Tokyo), the Gold Medal of the Max Bergmann Kreis (Munich), the first Gensia Lecturer, Frontiers in Chemistry Lecture Series [Scripps Clinic and Research Foundation (now The Scripps Research Institute)], the Alfred Burger Award (ACS), the Dr. Josef Rudinger Award of The European Peptide Society, the Edward E. Smissman Bristol Myers Squibb Award (ACS), the Arthur C. Cope Medal, in 2000, the presidential National Medal of Science awarded by President Clinton and in 2002, the Willard Gibbs Medal (Chicago Section, ACS). He is a member of the National Academy of Sciences, a Senior Fellow of the Institutes of Medicine of the National Academies, and a Fellow of the American Academy of Arts and Sciences.