Ion channels for non-experts
Ion channels are proteins embedded in all cell membranes of all
living organizms. 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
A typical cell has roughly 100-1,000 ion channels of
different types. Most ion channels transport only one specific ion.
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
Ion channels are important targets in drug discovery but
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.
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. The typical
throughput is three to ten successful patch clamp experiments per
day and requires patience and high level insight in
electrophysiology.
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.
Automated patch clamp technology - the
QPatch
The QPatch is the
name of Sophion's product family of automated patch clamp systems.
With the QPatch patch clamp experiments are done automatically with
much higher througput compared to the manual technique. 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 the 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, 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 humans in the
clinical phases of drug discovery.
The drug discovery revolution
Today traditional patch clamp technology is only used in the
initial target identification and validation phases and in the
final steps of lead optimization because of the very low
throughput.
When automated patch clamp systems, like the QPatch, are
systematically employed in all the relevant phases of ion channel
drug discovery, the process of ion channel drug discovery changes
dramatically changed. 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 the QPatch is leading a revolution in drug
discovery.