Hal Kohn, Ph.D., received a B.S. in chemistry from the University of Michigan in 1966 and a Ph.D. in chemistry from the Pennsylvania State University in 1971. He conducted postdoctoral research at Columbia University with Professor Ronald Breslow from 1971 to 1973. Kohn then joined the faculty of the Department of Chemistry at the University of Houston in 1973 before coming to the University of North Carolina in 1999 as Kenan Distinguished Professor. He retired from the UNC Eshelman School of Pharmacy in 2015 and currently holds the position of professor emeritus.
Broadly, two general themes defined Kohn’s research programs. The first is the elaboration of the mechanism of action of clinical agents. The second is the synthesis and evaluation of novel, new therapeutic agents. Both sets of studies were guided by the relationship of structure of the therapeutic agent with its function. Kohn’s studies utilized organic chemistry, biochemistry, molecular biology, structural biology, and computational chemistry and were enhanced by collaborative studies with UNC researchers and with other laboratories in the US and abroad. Laboratory personnel gained expertise in the disparate areas that encompass medicinal chemistry.
Specifically, Kohn and his coworkers examined in depth the mechanism of action of mitomycin C, bicyclomycin, and lacosamide. Kohn’s laboratory is credited with the discovery of lacosamide (Vimpat), a drug marketed worldwide by UCB Pharma for the treatment of partial (focal) seizures.
Epilepsy refers to the many types of recurrent seizures produced by paroxysmal excessive neuronal discharges in the brain. The mainstay of treatment has been the long-term and consistent administration of anticonvulsant drugs. Unfortunately, despite the many available therapeutic agents, none are capable of achieving total seizure control and most have disturbing side-effects.
Pharmacological studies in Khon’s laboratory have led to the discovery of a new class of highly stereoselective anticonvulsant agents termed “functionalized amino acids” (FAAs). The lead FAA discovered by us, (R)-N-benzyl-2-acetamido-3-methoxypropionamide (lacosamide, Vimpat), is a first-in-class antiepileptic agent, marketed in the United States and Europe for adjunctive treatment of partial-onset seizures in adults. Clinical investigations are underway for the use of lacosamide in monotherapy for partial seizures, children with partial seizures, and primary generalized tonic-clonic seizures.
Current studies in the Kohn laboratory are aimed at elucidating the key molecular determinants needed for lacosamide’s pharmacological activity. They are also investigating the mode of action of this novel drug. They have advanced a novel strategy to search the proteome for target sites where ligand (drug) binding is modest and where moderate-to-extensive ligand structural change abolishes target binding. This method has been utilized to interrogate the rodent brain proteome for lacosamide binding partners that explicate function and toxicity. Potential targets have been identified and these receptors are being validated. Novel proteomic tools have been developed to facilitate these studies. Among these is a readily available cleavable linker that permits high yield protein recovery under mild conditions from affinity supports (i.e., streptavidin).
New programs have been launched aimed at developing novel compounds that display broad activity in both seizure and pain models. In one of these, Kohn is working with the scientists at the NINDS Anticonvulsant Screening Program. Promising activities have been obtained in animal models.
Mitomycin C is a clinically significant antineoplastic agent. It is the prototype of an important class of anticancer compounds termed: bioreductive alkylation agents. Programs have been previously instituted to determine the molecular events leading to the activation and subsequent reaction of mitomycin C and mitomycin analogues, to elucidate the mode of action of the mitomycins in the presence of DNA, and to develop and evaluate a select series of biomechanistic analogues of mitomycin C.
Bicyclomycin is a structurally unique antibiotic which displays broad activity against a variety of Gram-negative bacteria. The mode of action of this clinical agent is poorly understood. We discovered that the site of bicyclomycin function is the essential enzyme in Escherichia coli, the rho transcription termination factor. Studies have been conducted that focused on determining the mechanism of the bicyclomycin, rho, and the bicyclomycin-rho interaction, as well as determining the role of rho in E. coli cell biology. Knowledge of this nature is expected to provide the molecular basis for subsequent research in this area and allow future general drug design to proceed on a less empirical basis.
Bacterial and mycobacterial infections remain an unmet health challenge. Resistance to conventional antibiotics constitutes a major health crisis. Tuberculosis alone accounts for 3.1 million deaths annually and an estimated one-third of the world’s population is infected. Recently, we showed that metal chelates are potent antibiotics and discovered that select hydroxamic acids are pathogen-specific inhibitors of Mycobacterium tuberculosis. We have information on the target site for each class of compounds.