This issue of Medicinal Chemistry Research is dedicated to the occasion of the 80th birthday of Emeritus Professor Ronald T. Borchardt for his many years of dedication to research, education, and service in the Departments of Medicinal Chemistry, Biochemistry, and Pharmaceutical Chemistry and School of Pharmacy at the University of Kansas (KU) and his broad, profound and lasting contributions to the advancement of drug discovery and development over an extraordinary career spanning half a century.

As a native of Wisconsin, Ron earned his Bachelor of Science in Pharmacy from the University of Wisconsin in Madison in 1967. His first course in organic chemistry proved pivotal to inspiring him to get involved in research, and he ultimately took on a project to extract potential anticancer agents from plants in the laboratory of Professor S. Morris Kupchan. Upon advice from a faculty mentor, Ron moved to KU for graduate studies under the guidance of Distinguished Professor and Chair of the Department of Medicinal Chemistry Edward E. Smissman, an academic leader in transforming medicinal chemistry and drug discovery into rational endeavors based on chemical principles.

In the Smissman group, Ron’s research involved the then cutting-edge concept of conformational restriction of neurotransmitters, to identify compounds that would bind more favorably to cognate receptors or enzymes. Ron developed conformationally restricted analogs of norepinephrine, dopamine, and acetylcholine that were transformed at different rates by their corresponding metabolizing enzymes (catechol-O-methyltransferase, or COMT, in the case of the adrenergic analogs, and acetylcholinesterase in the case of cholinergic analogs). Ron’s seminal three papers with Smissman in J. Med. Chem. reported their findings on the power of conformational restriction to fix ligands into shapes that are more complementary to the binding site on the cognate protein.

After earning his PhD in only three years, Ron then moved to NIH to work in the laboratory of Dr. Louis A. Cohen, a physical organic chemist who was developing a novel conformational restriction method called the “trimethyl lock”, in which three methyl groups are added to O-hydroxydihydrocinnamic acid to restrict the population of conformers and increase the rate of lactonization to form hydrocoumarin. During Ron’s short two years at NIH, he advanced this concept in a series of five papers published in JACS. The trimethyl lock became a versatile prodrug strategy for chemical biology and medicinal chemistry that is still employed over 50 years later. Remarkably, while at NIH Ron also learned enzymology in the laboratory of Dr. C. R. Creveling, working with COMT, the target of the conformationally restricted adrenergic analogs Ron had developed at Kansas.

In 1971, Ron moved back to KU as Assistant Professor of Biochemistry, publishing five papers on COMT within two years, four of which were single-author reports. He rapidly expanded his research into the broader topic of methyltransferases, establishing himself as a leader in this area. His growing research group designed, synthesized and evaluated inhibitors and affinity labeling reagents and conducted mechanistic studies on this important class of enzymes that play critical roles in biology and serve as key drug targets. Eight years after his return to KU, Ron was promoted to full professor, and in 1981 he was named the Solon E. Summerfield Distinguished Professor of Biochemistry and Medicinal Chemistry.

Ron’s group also deeply investigated the mechanism and inhibition of S-adenosyl-l-homocysteine (SAH) hydrolase. SAH is a product inhibitor of methyltransferases that use S-adenosyl-l-methionine as the methyl donor. SAH hydrolase was of keen interest because of its essential role in driving these methylations by removal of inhibitory SAH. This hydrolase was also considered a potential target for broad-spectrum antiviral activity, with evidence that its inhibition selectively blocked viral methyltransferases. Designed inhibitors of the enzyme served as mechanistic probes for the purified enzyme, chemical biological tools in cell culture, and potential therapeutics to treat viral infections. Ron was also an early adopter of structure-based drug design; in collaboration with colleague Dr. A. Vedani, his group conducted homology modeling of SAH hydrolase from the crystal structure of dogfish lactate dehydrogenase that could explain substrate binding, the binding and reactivity of cofactor NAD+, as well as the relative binding strength of inhibitors.

In 1983, Ron took on the role of chair of the KU Department of Pharmaceutical Chemistry from founding chair and Distinguished Professor Takeru Higuchi. In doing so, Ron also made the decision to shift his research to cellular and molecular pharmaceutics and pharmaceutical biotechnology. This appeared at the time to be a very risky move, but Ron approached this self-imposed challenge in the determined and systematic way that led to his great successes in inhibitor design and drug discovery. As it turned out, Ron’s approach to drug delivery was unique, as he thought about these problems as a medicinal chemist, in considering the cellular and molecular levels.

The first major problem in drug delivery Ron took on was the blood-brain barrier (BBB). His solution was to work toward a practical cell model system in a project spearheaded by postdoc Dr. Ken Audus (who went on to join the faculty and serve as chair of the department and dean of the KU School of Pharmacy). Although development of such a cell model system took several years, ultimately primary cultures of bovine brain microvessel endothelial cells proved successful, providing a means of studying nutrient and drug transcellular transport. This important advance was soon followed by the development of a cell culture model of the intestinal mucosa using human colon Caco-2 cells, in a project headed up by postdoc Ismael Hildago (who went on to co-found and lead the company Absorption Systems). These models were exploited by Ron’s group to understand the structural features of peptides and peptidomimetics to cross two major biological barriers (BBB and intestinal mucosa barrier) to drug delivery.

The formulation of “structure-transport relationships” using these cellular model systems of the BBB and the intestinal mucosa led Ron to develop general ideas about what makes a good drug versus a potent inhibitor or ligand and educating the pharmaceutical industry on the importance of this distinction. Ron spearheaded the development of a variety of workshops and courses focusing on designing drug for optimal in vivo activity after oral administration. In the process, he led efforts to get discovery research out of its siloed mentality and interact with preclinical and clinical development. The impact of Ron’s efforts to transform the drug discovery process in this way can hardly be overstated.

His contributions to pharmaceutical biotechnology are also profound. At a time when biotechnology was in its infancy, Ron secured an NIH Training Grant for graduate students to learn how to apply biotechnology to pharmaceutical problems. This training grant has been continuously funded by NIH to this day, 35 years from its inception in 1989. Ron initiated strategic faculty hires in this area, transforming the department and paving the way for success well into the 21st century. His group’s first foray into pharmaceutical biotechnology was in the study of peptide and protein stability, focusing on hydrolytic degradation, particularly of asparagine residues. Determination of the kinetics of these degradation reactions allowed elucidating the role of sequence, secondary structure, and formulations in affecting their rates. Later, Ron’s group also investigated mechanisms of peptide and protein oxidations to similar ends.

Ron’s lab, along with a network of collaborators, also made major advances in the design of prodrugs for peptides and peptidomimetics, which often had potent and specific interactions with their protein targets but poor intestinal absorption and BBB permeability. In formulating structure-transport relationships of peptides and peptidomimetics, Ron’s group noted that cyclization would improve permeability across these two critical biological barriers. Such cyclization would typically have a dramatic detrimental effect on target affinity, so Ron worked toward developing linker moieties that would allow for reversible cyclization, with conversion to the parent peptide/peptidomimetic after transport. A variety of successful linkers were identified, included “trimethyl-locked” phenylpropionic acid, which could link the N- and C-termini synthetically but be removed in vivo.

While advancing research in drug discovery and development in all these profound ways, Ron mentored 168 graduate students, postdoctoral trainees, and visiting scientists who worked in his laboratory. Many of these have gone on to their own high-impact careers in academia and industry. Ron also helped mentor and develop many young faculty at KU who became leading investigators in their own right. He served as a regular consultant to the pharmaceutical industry throughout his career, having a major impact on how the industry conducts drug discovery and the ability of biotech companies to develop successful peptide and protein therapeutics. His global influence can also be appreciated by his founding in 1996 of the Globalization of Pharmaceutics Education Network (GPEN), an international organization that brings together students and postdoctoral fellows from universities in the Americas, Europe and Asia and expose them to science and cultural on an international level. This organization continues to be a labor of love for Ron, who serves now as an emeritus member of the board of directors.

The above provides only a brief synopsis of the deep and broad impact Ron has had on research in drug discovery and development of both small molecules and biopharmaceuticals. Along the way, he educated and mentored many students, postdocs and visiting scientists who have gone on to make their own marks in the field and helped transform how industry discovers and develops drugs. A much more detailed description can be found in a tribute published by K.B. Schowen et al. in J. Pharm. Sci. in 2016 [1], and we highly encourage readers to turn to that commentary for a deeper appreciation for the remarkable contributions Ron has made in his incredibly prolific career.

Although all four of us have worked in Ron’s laboratory and benefited from his mentoring, we will end with an anecdote by one of us (Wolfe) that illustrates Ron’s approach to science as well as mentoring. When Mike was leaving KU for a postdoctoral fellowship at NIH, he sought career guidance from Ron. At NIH, Mike would be strictly doing biological research, with the idea that he would later mesh his training in chemistry and biology in establishing a multidisciplinary academic research laboratory, as his mentor had done. Mike asked Ron how he had gotten into new areas, particularly how he expanded his research into biology. He replied, “I just did it.” At the time, Mike didn’t find this very helpful, but later he realized what Ron was really saying: Don’t be afraid to get into new areas if you believe this is the best path forward. Be bold. Just do it. Through this special issue of Medicinal Chemistry Research, we offer our deep appreciation for Ron’s example of not just a medicinal chemist, but a scientist who went forward boldly into new areas.