Harold Kohn, PhD

Professor Emeritus

Research

Hal Kohn, Ph.D., received a B.S. in chemistry from the University of Michigan in 1966, and a Ph.D. in chemistry from Pennsylvania State University in 1971. He conducted postdoctoral research at Columbia University from 1971 to 1973 with Professor Ronald Breslow. Kohn then joined the faculty at the University of Houston in 1973 before coming to the University of North Carolina in 1999. He retired from the UNC Eshelman School of Pharmacy in 2015 and currently holds the position of professor emeritus.

Two general themes have 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 are guided by the relationship of structure of the therapeutic agent with its function. His work incorporates the examination of the biological mechanism of therapeutic agents (e.g., lacosamide, mitomycin C, bicyclomycin) at the molecular level and the design, synthesis and pharmacological evaluation of new therapeutic agents for the treatment of neurological disorders, cancer and bacterial infections.

Kohn’s laboratory focuses on the delineation of the mechanism of action of clinically approved and emerging drug candidates and in the broad disciplines of drug discovery and target identification and validation. On-going studies in the laboratory use organic chemistry, biochemistry, molecular biology, structural biology, and computational chemistry. Collaborative studies with UNC and national laboratories are in place and enhance our studies. Laboratory personnel gain expertise in the disparate areas that encompass medicinal chemistry.

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.

Publications

  • Hyosung Lee, Alexander S. Gold, Xiao-Fang Yang, Rajesh Khanna, and Harold Kohn,* Benzyloxybenzylammonium Chlorides: Simple Amine Salts That Display Anticonvulsant Activity. Bioorg. Med. Chem. 21, 7655-7661 (2013).
  • Ki Duk Park, Xiao-Fang Yang, Hyosung Lee, Erik Dustrude, Yuying Wang, Rajesh Khanna,* and Harold Kohn,* Discovery of Lacosamide Affinity Bait Agents That Exhibit Potent Voltage-Gated Sodium Channel Blocking Properties, ACS Chem. Neurosci., 4, 463-474 (2013).
  • Hyosung Lee, Ki Duk Park, Xiao-Fang Yang, Erik T. Dustrude, Rajesh Khanna, and Harold Kohn,* (Biphenyl-4-yl)methylammonium Chlorides: Potent Anticonvulsants That Modulate Na+ Currents, J. Med. Chem. 56, 5931-5939 (2013).
  • Amber King, Xiao-Fang Yang, Yuying Wang, Cindy Barbosa, Erik T. Dustrude, Michael R. Due, Andrew D. Piekarz, Sarah M. Wilson, Fletcher A. White, Christophe Salomé, Theodore R. Cummins, Rajesh Khanna,* and Harold Kohn,* Identification of the Benzyoxyphenyl Pharmacophore : A Structural Unit That Promotes Sodium Channel Slow Inactivation. ACS Chem. Neurosci., 3, 1037-1049 (2012).
  • Pranjal K. Baruah, Jason Dinsmore, Amber M. King, Christophe Salome, Marc De Ryck, Rafal Kaminski, Laurent Provins, Harold Kohn,* Synthesis, Anticonvulsant Activity, and Neuropathic Pain-attenuating of N-Benzyl 2-Amino-2-(hetero)aromatic Acetamides. Bioorg. Med. Chem. 20, 3551-3564 (2012).
  • Amber King, Marc De Ryck, Rafal Kaminski, Anne Valade, James P. Stables, and Harold Kohn,* Defining the Structural Parameters That Confer Anticonvulsant Activity by the Site-by-Site Modification of (R)-N’-Benzyl 2-Amino-3-methylbutanamide. J. Med. Chem. 54, 6432-6442 (2011). [PMCID: PMC3188959].
  • Amber King, Christophe Salomé, Elise Salomé-Grosjean, Marc De Ryck, Rafal Kaminski, Anne Valade, James P. Stables, and Harold Kohn,* Primary Amino Acid Derivatives: Substitution of the 4’-N-Benzylamide Site in (R)-N’-Benzyl 2-Amino-3-methylbutanamide and (R)-N’-Benzyl 2-Amino-3,3-dimethylbutanamide, and (R)-N’-Benzyl 2-Amino-3-methoxypropionamide Provides Potent Anticonvulsants with Pain Attenuating Properties. J. Med. Chem. 54, 6417-6431 (2011).
  • Amber King, Christophe Salomé, Jason Dinsmore, Elise Salomé-Grosjean, Marc De Ryck, Rafal Kaminski, Anne Valade, James P. Stables, and Harold Kohn,*  Primary Amino Acid Derivatives: Compounds with Anticonvulsant and Neuropathic Pain Protection Activities. J. Med. Chem. 54, 4815-4830 (2011).
  • Ki Duk Park, Dong Wook Kim, Onrapak Reamtong, Claire Eyers, Simon J. Gaskell,2 Rihe Liu* and Harold Kohn,* Identification of a Lacosamide Binding Protein Using an Affinity Bait and Chemical Reporter Strategy: 14-3-3 ζ. J. Am. Chem. Soc. 133, 11320-11330 (2011). [PMCID: PMC3148493].
  • Yuying Wang, Sarah M. Wilson, Joel M. Brittain, Matthew S. Ripsch, Christophe Salomé, Ki Duk Park, Fletcher A. White, J.P. Stables, Rajesh Khanna,* and Harold Kohn,,* Merging Structural Motifs of Functionalized Amino Acids and α-Aminoamides Results in Novel Anticonvulsant Compounds with Significant Effects on Slow and Fast Inactivation of Voltage-gated Sodium Channels and in the Treatment of Neuropathic Pain. ACS Chem. Neurosci. 2, 317 – 332 (2011). [PMCID: PMC3134314].