When Harold Kohn, PhD, joined the UNC School of Pharmacy in 1999, he ended a 26-year stint at the University of Houston.

Harold Kohn, PhD Kenan Professor Division of Medicinal Chemistry and Natural Products Research Interests Examination of the biological mechanism of mitomycin C and bicyclomycin at the molecular level; design and synthesis of new chemotherapeutic agents for the treatment of epilepsy, cancer, and bacterial infections

“I think it was a desire on my part for change for several reasons,” Kohn says. “Change is important, and it was a good time to do so because of both professional and personal reasons.

“I wanted to be part of a unit with more of a biological focus. I wanted to be on a campus that had a medical school nearby. Another reason why I wanted to change was that I wanted to take a leadership position. I felt I knew where where things should go programmatically, and I also felt that we all should return a little bit of the leadership we received over the years, and this was my turn.”

At UNC-Chapel Hill, Kohn found the biological focus and the medical school he was looking for, and he certainly has given back in terms of leadership. He chaired the School’s Division of Medicinal Chemistry and Natural Products for seven years before stepping down in 2006. He also has served as the director of the School’s Bill and Karen Campbell Faculty Mentoring Program since its inception in July 2006.

“The mentoring program has been a wonderful program for me to be a part of,” Kohn says. “There are things in life that have downsides along with the upsides, but this one is all up.”

Starting off on the Right Foot
While informal faculty mentoring has long been a part of academia, Kohn believes the School’s officially sponsored effort is the first of its kind among schools of pharmacy in the country. The program grew from the vision of former School dean Bill Campbell, who was a strong advocate of faculty mentoring.

Kohn says the program helps the School recruit, develop, and retain faculty, as well as engage the senior faculty in the mentoring process.

“There are so many pressures on our faculty that if there’s anything we can do to help and also to give our young faculty a competitive advantage in this very difficult funding period that we’re in, then we’re better off,” he says.

The voluntary program, supported by funds generated through the $1 million endowment of the Bill and Karen Campbell Professorship and funds from Dean Robert Blouin, pairs a junior faculty member with two mentors, who are either senior faculty from the School or people from other institutions or outside of academia.

“We believe that the mentoring team should be in place the minute the junior faculty member walks on campus,” Kohn says. “The time goes by very rapidly in a young faculty’s life, and the sooner that you can provide that help for them, the better off we believe they’d be.”

The mentors advise the junior faculty member on a wide range of subjects, such as balancing life and work, training graduate students, and interacting with colleagues in the School and the University. The team also helps the junior faculty member prepare for performance evaluations and conducts mock reviews of funding proposals.

“A lot of times you can strengthen you proposal by having a collaboration with another person, perhaps from the School of Medicine or the Department of Chemistry, but the young faculty often doesn’t know which people are around, so the mentoring team can help make those connections,” Kohn says.

Treating Epilepsy and Diabetic Neuropathy

When he was at the University of Houston, Kohn began working on lacosamide, an epilepsy and diabetic neuropathy drug. When he moved to UNC-Chapel Hill, he actually moved closer to a key partner in that area of his research. A few months after Kohn’s move, Schwarz Pharma, the German company that was conducting the clinical trials for his compound, opened an office in Research Triangle Park.

“It was just a fortuitous thing for me, but it also has been a good thing for me,” Kohn says.

Kohn, whose research focuses on the biological mechanism of action in clinically approved and emerging drug candidates, discovered lacosamide in 1996. The drug has passed Phase III clinical trials, and regulatory filing in the United States and Europe is expected in 2007.

Kohn’s research on the drug, however, is far from over. He is collaborating with Rihe Liu, PhD, an assistant professor in the School, on a National Institutes of Health-funded study to identify the binding sites for lacosamide in the brain.

“Lacosamide is a pretty interesting compound, and only recently have there been some reports of how it actually functions at the molecular level,” Kohn says. “These are very preliminary. The bottom line is that the full mechanism of action for lacosamide is not known. So we decided to look at our own compound.”

Kohn has also collaborated with division chair Alex Tropsha, PhD, in finding other new drugs to treat epilepsy. Tropsha specializes in computer-assisted drug design, and the collaboration combined research data from Kohn’s lab and computational methods from Tropsha’s lab to identify likely drug candidates.

“It was definitely a very enjoyable interaction with Alex where we took data from our anticonvulsants and, working with his laboratory, generated models that would allow you to identify the key structural elements that are necessary for anticonvulsory activities,” Kohn says.

“Then, using the algorithms, we mined a larger database of compounds and identified some novel structures that, at least to my eyes, would not have been projected to be structurally related to our compound.”

Kohn’s lab then prepared these compounds and sent them to an NIH testing lab for evaluation, which produced promising results.

“We had a significantly high percentage of compounds that had very nice activity, and it was activity that was predicted pretty well by the students [in Tropsha’s lab],” Kohn says. “We chose specifically to synthesize compounds that were as far removed as possible from my own working templates to test the computation method. I was very pleased with the results. We’ll need to further test those methods, but surely the initial results, which we published in a series of papers, were successful.”

Stopping the Gears in a Wheel

Kohn also has published some of the leading papers on the mechanism of action for the antibiotic bicyclomycin. His research revealed that the drug’s target in E. coli bacteria is the rho factor, a protein that is essential for telling the cell when to stop transcribing an RNA strand. Without the rho factor, the bacteria would not know when to terminate transcription, thus rendering whatever RNA strands they produce useless.

What makes the rho factor an even more appealing drug target is the fact that it does not exist in human cells, thus negating any concern about bicyclomycin’s toxicity to patients.

“Basically what happens is bicyclomycin binds to the rho protein, and just like interrupting the spokes or gears of a wheel, it prevents it from moving,” Kohn says. “It’s a pretty mechanism.

“It causes the bacteria to utilize valuable energy in making unwanted cell transcripts, which is not helpful for the bacteria.”