What is Ion Channels?

Ion channels allow the movement of charged particles, known as ions, across cell membranes. Ion channels function in a variety of biological pathways including the firing of neurons and muscle cells and the activation of immune cells.

Overview

Ion channels are used to restore the balance of ions across a membrane. When open, ion channels allow charged molecules to move from an area of high concentration to low concentration without using energy. Ion channels serve as a counterbalance to active transport, a process whereby a cell uses energy to actively pump ions and other charged molecules across a membrane in order to establish ion gradients or alter the pH of an organelle to activate enzymes. There are two major types of ion channels:

  • Voltage-gated ion channels
  • Ligand-gated ion channels

When ions are present in a higher concentration on one side of a membrane than the other, a difference in voltage occurs across that membrane, creating a membrane potential. Voltage-gated ion channels open in response to a change in membrane potential, allowing the ions to move from the side of the membrane with the higher ion concentration to the side with the lower ion concentration.

Ligand-gated ion channels rely on the binding of a small molecule to the channel. The small molecule binding causes a change in the channel protein, opening the pore for the ions to travel through. As with voltage-gated ion channels, when ligand-gated ion channels open ions move from the side of the membrane with the higher ion concentration to the side with the lower ion concentration.

When targeted by therapeutics, ion channels are either inhibited, preventing the flow of ions, or held constitutively open by the action of agonists, preventing the accumulation of ions on one side of the membrane. The desired activity of the ion channel modulator depends on the disease being targeted.

Existing Products

There are several ion channel modulators currently in use. Examples are included in the table below.

Channel Type Target Name Development Status
Voltage-gated Ca2+ channel Multiple FDA approved anti-hypertensives
Nachannel Multiple FDA approved products including local anaesthetics and anticonvulsants
Kchannel Multiple sulfonylureas approved for diabetes
Ligand-gated Glutamate-gated chloride channel Ivermectin, FDA approved for onchocerciasis and in use for the treatment of lymphatic filariasis
Acetylcholine-gated chloride channels Levamisole, pyrantal, and tribendamadine (China only), for treatment of helminth infections

Multiple FDA approved products for the treatment of tobacco dependence

Ion Channel Modulators as Non-Neglected Tropical Disease Therapeutics

Ion channel inhibitors are used to treat a wide range of conditions including:

  • Hypertension
  • Pain
  • Convulsions
  • Diabetes
  • Tobacco dependence

The most well-known and widely-used ion channel inhibitors are the calcium channel inhibitors used to treat high blood pressure. The movement of calcium across cell membranes causes muscle contractions. While this is a normal biological process, contraction of the muscles of the circulatory system can exacerbate the condition of patients with high blood pressure or hypertension. Calcium channel blockers are used in patients with hypertension to reduce contraction of the smooth muscles of the arteries, allowing the arteries to dilate to reduce blood pressure.

Ion Channel Modulators as Neglected Tropical Disease Therapeutics

Ion channel inhibitors are used to treat parasitic worm infections including:

  • Onchocerciasis
  • Lymphatic filariasis
  • Ascariasis
  • Hookworm
  • Schistosomiasis

Ivermectin is a glutamate-gated chloride channel inhibitor that is widely used in mass drug administration programs in the developing world to treat infections with parasitic worms that cause onchocerciasis and lymphatic filariasis.1,2 Ivermectin is also used widely in veterinary medicine for the treatment of worm infections.3 The drug is believed to work in these organism by inhibiting glutamate-gated chloride channels, which are only found in invertebrates, allowing these drugs to selectively target parasitic worms over their human hosts.4 Disruption of the flow of chloride causes paralysis and starvation of the worm leading to death.

Levamisole and pyrantal pamoate can be used to treat the soil transmitted helminths ascariasis and hookworm, but are not widely used. Tribendamadine is used to treat ascariasis in China but has not been extensively evaluated or used outside of China. All three of these products are agonists of acetylcholine-gated chloride channels.5 These drugs force the chloride channels to remain open rather inhibiting them; the resulting imbalance of chloride ions results in death of the worms.

Praziquantel is the only on market drug for the treatment of schistosomiasis. Although the mechanism of action of praziquantel is not entirely clear, it is believed that the drug inhibits calcium channels on the parasite.6 More research is needed to understand if inhibition of calcium channels is the primary mechanism of action of praziquantel or part of a multi-target mechanism.

References

  1. WHO NTD Report 2010
  2. Keiser J and Utzinger J (2010) “The drugs we have and the drugs we need against major helminth infections.” Advances in Parasitology73: 197-229.
  3. Raymond V and Sattelle DB (2002) “Novel animal-health drug targets from ligand-gated chloride channels.” Nature Reviews: Drug Discovery 1: 427-436.
  4. Geary TG (2005) “Ivermectin 20 years on: maturation of a wonder drug.” TRENDS in Parasitology 21: 530-532.
  5. Hu Y et al. (2009) The New Anthelmintic Tribendimidine is an L-type (Levamisole and Pyrantel) Nicotinic Acetylcholine Receptor Agonist.PLoS NTD 3: e499.
  6. Doenhoff MJ et al. (2008) “Praziquantel: mechanisms of action, resistance and new derivatives for schistosomiasis.” Curr Opin Infect Dis21: 659-667.

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Pipline

Analysis

Modulators of ion channels have been validated as therapeutic targets for a variety of diseases included parasitic worms. Ion modulators are challenging to study as a target class, but advances in non-neglected disease applications of ion channel modulators have the potential to inform development of new neglected disease products. Additionally, modulators of ion channels have the potential to benefit from the recycling of chemical compound libraries developed through previous drug development programs or parallel development of compounds for non-neglected disease applications.

The relative strengths, weaknesses, opportunities and risk for ion channel modulators that are currently in development for neglected diseases are summarized here.

  Strengths Weaknesses Opportunities Risks
Ligand-gated ion channels: Glutamate-gated chloride channels
Relevant neglected tropical diseases:

Onchocerciasis (Moxidectin, phase III)
In use for the treatment of heartworm in animals

Based on proven mechanism of action for treatment of helminth infections
Because same mechanism of action as ivermectin, unlikely to overcome limitations faced by ivermectin Potential for use in the treatment of other helminth infections such as lymphatic filariasis May be susceptible to the same mechanisms of resistance as ivermectin
Ligand-gated ion channels: ATP-gated anion channel
Relevant neglected tropical diseases:

Diarrheal diseases (crofelemer, phase II; iOWH032, phase I; Second-generation synthetic CFTR chloride channel inhibitors, pre-clinical)
Because target is in the intestine, can deliver drug orally with no need for systemic distribution

Crofelemer already in phase III for irritable bowel syndrome
  Potential to benefit from parallel research programs with cystic fibrosis, a genetic disorder caused by malfunctioning CFTR

Potential for combination with oral rehydration therapy or organism specific treatments
Malfunctioning CFTR results in cystic fibrosis. Although poor bioavailability outside of the intestine limits risks with crofelemer, risks for toxicity are a concern.

Crofelemer is already in phase II, not clear what the competitive advantages of backup/alternative programs are 

Current standard of care for diarrhea is oral rehydration therapy, not clear how difficult it will be to change this policy to allow use of a product such as crofelemer
Ligand-gated ion channels: Calcium-gated chloride channel
Relevant neglected tropical diseases:

Diarrheal diseases (crofelemer, phase II)
Because target is in the intestine, can deliver drug orally with no need for systemic distribution

Crofelemer already in phase III for irritable bowel syndrome
  Potential development of combination products with CFTR inhibitors

Potential for combination with oral rehydration therapy or organism specific treatments
As CFTR is the primary target of crofelemer, it is unclear if CaCC also needs to be inhibited for effects

Current standard of care for diarrhea is oral rehydration therapy, not clear how difficult it will be to change this policy to allow use of a product such as crofelemer
Other: Plasmodial surface anion channel (PSAC) inhibitor
Relevant neglected tropical diseases:

Malaria (ISPA-028)
Target unique to malaria 

Inhibitors can selectively target drug resistant parasites
Susceptibility to inhibitors appears to vary by parasite strain, may be susceptible to resistance or require more work to identify broadly effectively lead compound

More understanding of the basic biology of this channel type is needed
Because channel is unique to the parasite, potential to develop highly selective drug. However, because the channel is unique the chances of repurposing existing ion channel inhibitors is lower. Variability of channel susceptibility to inhibitors between parasite strains suggests risk of developing resistance is high

Chemical libraries of ion channel modulators developed for non-neglected diseases may be useful for new drug discovery for neglected diseases. Potential ion channel drug targets for neglected diseases are described below.

Neglected tropical disease Voltage-gated ion channels Ligand-gated ion channels
Soil transmitted helminths: ascariasis, trichuriasis, hookworm   Glutamate-gated chloride channel inhibitors and Acetylcholine-gated chloride channel agonists1,2 

Although ivermectin is less effective against these organisms, additional research may identify more potent analogs of ivermectin or moxidectin. Also there is potential for repurposing of compound libraries developed for nicotine addiction.
Other helminths: onchocerciasis, lymphatic filariasis   Glutamate-gated chloride channel inhibitors and acetylcholine-gated chloride channel agonists1,2

Targets validated with on market products. May benefit from repurposing of compound libraries developed for nicotine addiction
Diarrheal diseases   Host CFTR and CaCC

Potential for co-development of products with research programs for cystic fibrosis and/or non-infectious diarrhea (e.g. irritable bowel syndrome)
Malaria Classical voltage-gated ion channels have not been identified. Plasmodial surface anion channel
(PSAC)3
Schistosomiasis Ca2+ channels4

Potential repurposing of calcium channel blockers developed for hypertension
 

References

  1. Keiser J and Utzinger J (2010) “The drugs we have and the drugs we need against major helminth infections.” Advances in Parasitology73: 197-229.
  2. Raymond V and Sattelle DB (2002) “Novel animal-health drug targets from ligand-gated chloride channels.” Nature Reviews: Drug Discovery 1: 427-436.
  3. Nguitragool W et al. (2011) “Malaria Parasite clag3 Genes Determine Channel-Mediated Nutrient Uptake by Infected Red Blood Cells.”Cell 145: 655-677
  4. Doenhoff MJ et al. (2008) “Praziquantel: mechanisms of action, resistance and new derivatives for schistosomiasis.” Curr Opin Infect Dis21:659-667.

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To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.

Database Resources

Ion channels are more difficult to study than other enzymatic drug targets. Early research on the function of ion channels was made possible through the use of potent naturally occurring neurotoxins such as those found in spider and snake venom. The potential for therapeutics targeting ion channels has led to significant advances in the tools and techniques available for ion channel targeted therapeutics.

There are several databases with general information on ion channels, including:

Assays

Tools available for ion channel drug development have been reviewed in the scientific literature.1,2 Common assays include:

  • Membrane binding assay
  • Electrophysiology (including patch-clamp)
  • Ion flux assays
  • Fluorescent dyes
  • Fret-based assays

The majority of these assays have been adapted to high throughput formats, however not every ion channel type generates enough signal for robust high throughput screening.

References

  1. Zheng W and Kiss L. “Screening Technologies for Ion Channel Targets in Drug Discovery.” American Pharmaceutical Review, availablehere.
  2. Owen D and Silverthorne A. “CHANNELLING DRUG DISCOVERY: current trends in ion channel drug discovery research.” Drug Discovery World, Spring 2002.

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.