Daniel H. Rich
Professor of Medicinal and Organic Chemistry, University of Wisconsin - Madison
Nature’s Peptide Mimetics. Unique Structures. Surprising Properties.
When I arrived at the University of Wisconsin in 1970, I knew I wanted to apply my organic chemistry training in peptides to combating human disease. Exactly how I was going to do that was not at all clear and many colleagues (and companies) thought it was not feasible. We all knew that peptide chemistry and its related biology were fascinating and important research areas, but no orally-active drugs had been developed from them, primarily because peptides are notoriously short lived in vivo and poorly bioavailable. And there weren’t any obvious targets at the time. My goal was deemed very high-risk.
Teaching medicinal chemistry at UW-Madison, and interacting with many superb UW biologists, broadened my perspective. I learned that the penicillin and cephalosporin antibiotics were created from peptide-derived natural products. More importantly, their mechanism of action suggested that the beta-lactam antibiotics were among the first of what came to be called mechanism-based inhibitors. I also learned the difference between direct and indirect acting drugs; the latter produced their effect by inhibiting metabollic enzymes that raised or lowered endogenous messenger levels. From these examples I surmised that peptide-derived natural products that inhibited enzymes effecting human disease could be modified to produce orally active drugs, and I began to search actively for suitable candidates to work on.
Fortunately for me, in 1970 Hamao Umezewa began publishing the results of a systematic search to identify novel natural products that inhibited mamalian enzymes. One of the first reported was pepstatin (1), a unique hexapeptide that strongly inhibited several aspartic peptidases. However renin, the aspartic protease central to regulation of blood pressure, was weakly inhibited. Pepstatin contained a unique amino acid, 3-hydroxy-4-amino-6-methylhexanoic acid (Sta, 2), and preliminary data suggested that portions of the Sta 2 residue were needed for potent inhibition. Soon thereafter Miller et al at Eli Lilly reported in 1972 that pepstatin lowered blood pressure in rats, a surprising result because 1 was not very potent against renin. Pepstatin thus appeared to me to be the peptide derived inhibitor I needed to explore my drug design strategy. Novel anti-hypertensive agents became our first target, with the goal to develop potent, selective inhibitors of renin and not other enzymes.
Over the next 35 years my group synthesized many novel enzyme inhibitors based on peptide-derived natural products. These included analogs of pepstatin, tentoxin, chlamydocin, cyclosporine and many others. We approached each target by synthesizing analogs, and interpreting their kinetic, conformational, and biological properties in terms of detailed structure, while developing new synthetic methods as needed. Positive therapeutic results were obtained in some cases, but more importantly we often were totally surprised by where the research led. A major example was the discovery that HIV protease was inhibited by statine-like inhibitors created for the renin inhibitor industrial programs.
But selective inhibition of a target enzyme did not always produce the therapeutic result desired. Inhibitors of beta-secretase designed to suppress formation of beta-amyloid have not yet shown efficacy in Alzheimer’s disease, possibly because beta-amyloid is an antimicrobial peptide in the innate immune system. In another example, our synthesis of cyclosporin analogs suggested that inhibition of Peptidy Prolyl cis trans isomerase was not needed for immunosuppression. In both cases shifting targets led to shifting paradigms.
My work did indeed follow a complex “trail of research”, a phrase coined by Vincent duVigneaud to describe how scientists explore ideas like Lewis & Clark explored the Pacific Northwest. In my lecture I will describe our successful early work as well as some of the pathways we initiated that are still being pursued productively by others even today.
I am most grateful to the National Institues of Health for their sustained financial support given me during my career. Without it, little of my work would have been possible.
Dr. Daniel H. Rich, Emeritus Ralph F. Hirschmann Professor of Medicinal And Organic Chemistry at the University of Wisconsin-Madison was a General Motors Scholar at the University of Minnesota-Minneapolis from 1960-64 where he received the B. Chemistry degree in 1964. He received his Ph. D. in organic chemistry from Cornell University and held postdoctoral appointments with Vincent du Vigneaud and W. S. Johnson (Stanford) before joining the Faculty in Pharmacy at the University of Wisconsin-Madison in 1970. His research focused on the synthesis and conformational analysis of cyclic peptides, and the design and synthesis of inhibitors of therapeutically important enzymes, especially aspartic proteases. His work in the aspartic protease field laid the ground-work for the development of the HIV protease inhibitors used to treat AIDS. He published over 250 articles and trained 36 PhD students and another 100 postdoctoral students; many of his students rose to important research positions in the pharmaceutical industry.
His research accomplishments have been recognized by the 1990 Vincent du Vigneaud Award in Peptide Chemistry, the 1992 ACS Division of Medicinal Chemistry Award, the 1992 Research Achievement Award of the American Association of Pharmaceutical Scientists, the 1992 George Herbert Hitchings Award for Innovative Methods in the Design and Discovery of Drugs, the 1993 ACS Ralph F. Hirschmann Award in Peptide Chemistry, a WARF University Professorship at UW-Madison in 1994 (which he named after Ralph F. Hirschmann), the E. Volwiler Research Achievement Award from the Amer. Assoc. Colleges Pharmacy in 1995, an Arthur C. Cope Scholar Award from the American Chemical Society in 1999 and the R. Bruce Merrifield Award from the American Peptide Society in 1999, and the E. E. Smissman Award from the ACS Division of Medicinal Chemistry in 2005. In 1993, he was a Senior U.S. Scientist Alexander von Humboldt Scholar in Germany. In 2004, he was awarded an Outstanding Alumni Achievement Award from his alma mater, the Institute of Technology of the University of Minnesota and in 2007 was placed on the ACS Medicinal Chemistry Hall of Fame
Professor Rich was elected Teacher of the Year by the UW-Madison Pharmacy graduating class of 1986 for his teaching of Medicinal Chemistry. From 1989 till his retirement in 2006 he lectured each year at the Drew University Residence School in Medicinal Chemistry on the design of enzyme inhibitors and peptidomimetics. In addition, Professor Rich has presented short courses in Medicinal Chemistry to pharmaceutical societies in Sweden, England, Japan and other foreign countries. He presented about 20 invited lectures each year, nationally and internationally. Professor Rich also served as a consultant in drug-design and discovery, especially in the area of design of protease inhibitors, for many major pharmaceutical companies.
Professor Rich served in administrative roles at UW-Madison. From 1976-1980 he was Assistant Dean of Graduate Studies in the School of Pharmacy. He served as elected member of the Physical Sciences Divisional Committee for UW-Madison from 1991-1993 and chaired the committee in 1992-1993. He was appointed to the UW-Madison Graduate School Research Committee (Biology Division) from 1994 to 1997. He also served as a member of the honorary degrees committee for UW-Madison from 1995-1998. He organized and wrote the first Chemistry-Biology Interface training grant for UW-Madison in 1992 and served as its program director, principle investigator and chair of the advisory committee from 1993-2003; the UW-Madison CBI training program remains the largest of its type in the United States. From 2005-2006, he was Associate Dean for Research and Graduate Studies for the School of Pharmacy.
At the national level, Professor Rich was President of the American Peptide Symposium from 1979-1981, a member of the Bioorganic and Natural Products study section for NIH from 1981-1985 and Chairman of that study section from 1983-1985, a Fellow of the American Association for the Advancement of Science since 1986, and a council member for the American Peptide Society. He was Associate Editor for the Journal of Medicinal Chemistry from 1988-1992, and was Associate Editor of the ACS journal, Organic Letters, from 1999 through 2005.
Professor Rich was active within the Medicinal Chemistry Division of the American Chemical Society. He was Chairman for the Division of Medicinal Chemistry in 1992, served as a member of the Planning Committee, organized two Symposia for the Division, and was an Academic Councilor for the division. He organized the 29th National Medicinal Chemistry Symposium held June 27-July 2, 2004 in Madison WI.