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.