Ion channels are vital for all life
Ion channels are proteins embedded in all cell membranes of animals and plants. They are responsible for transport of ions (i.e., ‘salt’) across the cell membranes, and are crucial for all physiological processes. Examples of such processes are:
- Generation of electrical activity in
nerves - Control of contractile activity in the
heart and muscles - Nutrient uptake
- Hormone secretion
There are many ion channels – most are not fully known
A typical cell has roughly 100-1,000 ion channels of different types. Most ion channels transport only single ionic species or a group of ions. This is reflected in the common names of the ion channels, e.g., K+, Na+, Ca2+ and Cl- ion channels.
The sequencing of the human genome has recently led to the identification of more than 400 putative ion channels. Today, only about 100 of these have been cloned and functionally tested.
Ion channels play a role in many diseases
A number of human diseases, including cystic fibrosis, epilepsy and a variety of neural and muscular disorders, are caused by defects in the function of ion channels.
Many drugs affect ion channels
The large number of physiological processes regulated by ion channels and their role in many diseases make ion channels highly interesting as targets for new drugs. Today about 20% of all registered drugs target ion channels. The drugs modulate specific ion channels, resulting in altered cellular behavior.
Ion channels are difficult to explore
However, even though ion channels are highly “druggable-,” targets they are also difficult to study. Despite significant research efforts, there is still limited know-how about ion channel function and how ion channels are related to specific diseases. This is mainly a result of the limitations and complexity in existing technologies available for ion channel research. Therefore ion channels are considered largely unexploited compared to other target classes, for example the G-protein coupled receptors (GPCRs) or kinases.
Methods to explore ion channels
There are two main methods to explore ion channels: direct and indirect methods. The only direct method is called patch clamp. In brief, patch clamp is very accurate, but also very time consuming (i.e., has low throughput), while the indirect methods are less accurate, but typically much faster.
Patch clamp
The patch clamp technique is considered the gold standard in ion channel research. The technique was developed by Erwin Neher and Bert Sakmann in the 1970's, who received the Nobel Prize in Physiology and Medicine (1991) for their work. In a traditional patch clamp experiment, the cell membrane is manually ruptured by a tiny glass pipette. Via an electrode in the glass pipette, the tiny current through the ion channels can be measured. A typical throughput is three to ten successful patch clamp experiments per day, and this usually requires Ph.D.-level expertise to operate the instrument.
Indirect methods to study ion channels
There are several indirect methods for studying ion channels. The most important indirect methods are fluorescent-based technologies. These technologies are based on fluorescent dyes that are loaded into cells and then analyzed using specialized plate readers. The readers detect a changed concentration of certain ions, which are the result of ion channel activity. The main benefits of these methods are their high throughput and low cost per datapoint. The main limitations of the methods are less accurate measurements and typically low sensitivity, making it possible to study only certain types of ion channels.
New and promising technology - QPatch
QPatch is the name of Sophion’s product family of automated patch clamp systems. Based on advanced microtechnology, QPatch systems potentially increase patch clamp throughput from 100 up to 1,000 times by a high degree of parallelism and automation. Thus QPatch combines the accuracy of traditional patch clamp with the high throughput of indirect methods. Speed and accuracy of automated patch clamp systems are heavily demanded by pharmaceutical companies working with development of ion channel-based drugs.
The drug discovery process in short
The drug discovery process in pharmaceutical companies begins with identifying potential targets for new diseases. One important class of targets is ion channels. After a target validation phase, a test system (an assay) is developed for measuring interactions with the target. Pharmaceutical companies have huge libraries of chemical compounds for potential stud, the largest of which contain up to several million compounds. One or more of these compounds may be a potential drug that has exactly the desired interaction with the target. It is like finding a needle in a haystack! Normally the entire compound library or part of it is screened with indirect methods in a so-called HTS (High Throughput Screening) department in the pharmaceutical company. The screening leads to a number of "hits" having some kind of desired interaction with the target. The hits are normally further validated before they become so-called lead compounds. The lead compounds are optimized in an iterative process known as lead optimization, in which chemists synthesize a number of new compounds with more optimal properties than the initial lead compounds. The best of the leads are identified and tested in disease-related animal models. Finally, in the safety phase, the optimized lead compounds undergo extensive testing for possible unwanted side effects. Compounds that pass this last test are called drug candidates and are further tested in human beings in the clinical phases of drug discovery.
The drug discovery revolution
Today, because of the very low throughput of traditional patch clamp, this technology is only deployed in the initial target identification and validation phases and in the final steps of lead optimization.
When automated patch clamp systems, like QPatch, are systematically employed in all relevant phases of ion channel drug discovery, it dramatically changes the process of ion channel drug discovery. Some of the phases of the drug development process (assay development and hit validation) can be virtually eliminated, while others (lead optimisation and safety pharmacology) can be significantly shortened. At the same time, lead compounds of higher quality emerge. The result is expected to be the development of more and also more efficient ion channel-based drugs, in addition to a 20%-50% shorter pre-clinical development timeline.
More and better leads…faster. That’s why we say QPatch is leading a revolution in drug discovery.
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