Research Synopsis

Examination of the biological mechanism of therapeutic agents (e.g., lacosamide, mitomycin C, bicyclomycin) at the molecular level; design, synthesis, and pharmacological evaluation of new therapeutic agents for the treatment of neurological disorders, cancer, and bacterial infections.

Hal Kohn received a BS in chemistry from the University of Michigan in 1966, and a PhD in chemistry from Pennsylvania State University in 1971. He  conducted postdoctoral research at Columbia University from 1971 ot 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.

Research Interests

Two general themes have earmarked 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.

Antiepileptic Agents: Drug Discovery and Mode of Action

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).

Development of New Neurological Agents

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: Mode of Action of a Clinical Anticancer Drug

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: Mode of Action of a Novel Antibiotic

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.

Development of New Antibacterial and Antimycobacterial Agents

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.

Ten Most Recent Publications

1. Defining the Structural Parameters that Confer Anticonvulsant Activity by the Site-by-Site Modification of (R)-N'-Benzyl 2-Amino-3-methylbutanamide. King AM, De Ryck M, Kaminski R, Valade A, Stables JP, Kohn H. J Med Chem. 2011 Aug 23. [Epub ahead of print] nPMID: 21861466 [PubMed - as supplied by publisher]
2. Primary Amino Acid Derivatives: Substitution of the 4'-N'-Benzylamide Site in (R)-N'-Benzyl 2-Amino-3-methylbutanamide, (R)-N'-Benzyl 2-Amino-3,3-dimethylbutanamide, and (R)-N'-Benzyl 2-Amino-3-methoxypropionamide Provides Potent Anticonvulsants with Pain Attenuating Properties.King AM, Salome C, Salome-Grosjean E, De Ryck M, Kaminski R, Valade A, Stables JP, Kohn H. J Med Chem. 2011 Aug 23. [Epub ahead of print] PMID: 21861463 [PubMed - as supplied by publisher]
3. Identification of a Lacosamide Binding Protein Using an Affinity Bait and Chemical Reporter Strategy: 14-3-3 ζ. Park KD, Kim D, Reamtong O, Eyers C, Gaskell SJ, Liu R, Kohn H. J Am Chem Soc. 2011 Jul 27;133(29):11320-30. Epub 2011 Jul 6. PMID: 21692503 [PubMed - in process]
4. Primary amino acid derivatives: compounds with anticonvulsant and neuropathic pain protection activities. King AM, Salomé C, Dinsmore J, Salomé-Grosjean E, De Ryck M, Kaminski R, Valade A, Kohn H. J Med Chem. 2011 Jul 14;54(13):4815-30. Epub 2011 Jun 15. PMID: 21639114 [PubMed - in process]
5. 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. Wang Y, Wilson SM, Brittain JM, Ripsch MS, Salomé C, Park KD, White FA, Khanna R, Kohn H. ACS Chem Neurosci. 2011 Jun 15;2(6):317-322. PMID: 21765969 [PubMed]
6. Development and characterization of novel derivatives of the antiepileptic drug lacosamide that exhibit far greater enhancement in slow inactivation of voltage-gated sodium channels. Wang Y, Park KD, Salome C, Wilson SM, Stables JP, Liu R, Khanna R, Kohn H. ACS Chem Neurosci. 2011 Feb 16;2(2):90-106. PMID: 21532923 [PubMed]
7. The structure-activity relationship of the 3-oxy site in the anticonvulsant (R)-N-benzyl 2-acetamido-3-methoxypropionamide. Morieux P, Salomé C, Park KD, Stables JP, Kohn H. J Med Chem. 2010 Aug 12;53(15):5716-26. PMID: 20614888 [PubMed - indexed for MEDLINE] Free PMC Article
8. Proteomic searches comparing two (R)-lacosamide affinity baits: An electrophilic arylisothiocyanate and a photoactivated arylazide group. Park KD, Stables JP, Liu R, Kohn H. Org Biomol Chem. 2010 Jun 21;8(12):2803-13. Epub 2010 Apr 19. PMID: 20405068 [PubMed - indexed for MEDLINE]
9. Merging the structural motifs of functionalized amino acids and alpha-aminoamides: compounds with significant anticonvulsant activities. Salomé C, Salomé-Grosjean E, Stables JP, Kohn H. J Med Chem. 2010 May 13;53(9):3756-71. PMID: 20394379 [PubMed - indexed for MEDLINE] Free PMC Article
10. Synthesis and Anticonvulsant Activities of N-(4’-Substituted)benzyl (R)-2-Acetamido-3-methoxypropionamides. Christophe Salome, Elise Salome-Grosjean, Ki Duk Park, Pierre Morieux, Robert Swendiman, Erica DeMarco, James P. Stables, and Harold Kohn,* J. Med. Chem. 53, 1288-1305 (2010). [PMID 20041718; PMCID 2818974]