Mechanism of new anticonvulsant unraveled: how it “sticks” to the target
Epilepsy is a common disorder, affecting 1 in every 100 people worldwide. However, an overwhelming number of patients develop resistance to common medications, requiring new classes or improved versions of existing drugs. In the latter case, understanding how the drug works is crucial. What is its target? Which part of the target does it interact with? What type of chemical interaction is involved?
Researchers have now unraveled the mechanism of an emerging class of anticonvulsant at an atomic scale. In a new study published in Nature Communications, the researchers identify a chemical interaction that is essential for the action of the anti-epileptic drug, retigabine.
“We have used unnatural amino-acid mutagenesis to subtly rearrange atoms and electrons [at] the retigabine binding site,” the study reports. “[Our findings] pinpoint specific atoms and chemical forces involved in retigabine interactions, and highlight approaches that may be used to guide rational improvement of existing drugs.”
Retigabine is known to interact with one of the amino acid residues, or building blocks, of its target protein. The new study reveals that the drug action relies strongly on a type of chemical interaction, called hydrogen bond or H-bond, between the drug and the amino acid residue.
The anticonvulsant binds to the target through a single hydrogen bond, like a weak magnet. When the researchers swapped the amino acid residue with an unnatural amino acid lacking the ability to form H-bond, the drug action was abolished. They then substituted the amino acid with fluorinated analogues that are able to form stronger H-bond, just like a stronger magnet. This time, they observed that the drug potency was strengthened.
“These [findings] pinpoint specific atoms and chemical forces involved in retigabine interactions, and highlight approaches that may be used to guide rational improvement of existing drugs,” the researchers conclude.
The researchers were motivated to investigate the anti-epileptic drug by the patient needs. “…[E]ven though epilepsy affects about 1% of the population, a third of these patients do not respond to currently available medicines, highlighting the need to explore novel mechanisms and targets,” says Robin Kim, a PhD student at University of British Columbia and one of the major contributors of the new study.
Many vital functions in the body are regulated by plug-like proteins, called ion channels. These channels act like gates that allow passages of certain ions between different cellular compartments. There are various types of channels that specialize in the passages of selective ions and are responsible for diverse functions – from memory formation to muscle contraction.
When channel performance goes awry (for example, becoming leaky or not opening the gate at the proper moment), it results in various disorders, such as epilepsy. Not surprisingly, a large number of medications work by targeting ion channels, either suppressing or stimulating them.
Traditionally, anti-epileptic drugs target channels selective for sodium ions. However, many patients have developed resistance towards this type of drugs. For this reason, new drugs have started to diversify their targets. A recently approved anticonvulsant, retigabine, for example, targets channels selective for potassium ions.
“Among all the antiepileptic drugs in use, retigabine has a unique mechanism—it is the only compound approved for human use that acts by [targeting potassium] channels,” the researchers say.
While previous studies identified that the drug interacts with a conserved amino acid residue in the channel’s pore-forming region (or its “business end”), detailed understanding of the molecular mechanism had been insufficient until now.
Retigabine may have broad applications, according to previous research. The drug is potentially effective in treatment of painful syndromes, hypertension, cardiac arrhythmias, tinnitus, Parkinson’s disease, and Huntington’s disease. Furthering our understanding of the drug, thus, might benefit hundreds of millions of people affected by the said conditions.
The new study was led by Harley Kurata, a researcher from Life Sciences Institute and Department of Anesthesiology, Pharmacology, and Therapeutics at University of British Columbia (who is currently at Department of Pharmacology, University of Alberta). In addition to researchers in Canada, the team consisted of international collaborators from University of Iowa (US), University Hospital Münster (Germany), and University of Copenhagen (Denmark).
The report appears this month on Nature Communications and is open access (no subscription fee).