The positives and negatives of ion channel targets
Ion channels are membrane proteins that are present in almost all living cells. As well as controlling ion flow across the cell membrane, they are also key in modulating certain diseases. However, it wasn’t until the mid-2000s that specific ion channels became an interesting target for pain drug discovery.
“New genetic data, at the time, showed ion channel Nav1.7 as a really hot topic for pain, because people with a congenital mutation in this ion channel had no pain. The only other symptom they had was a loss of smell. But everything else functioned as usual, which showed Nav1.7 as being a top target”, says Steve.
With these promising findings, research into the area took off and treatments targeting ion channels were investigated. However, technical challenges meant that ion channel research started to flounder, and the industry started to focus on alternative targets.
“While ion channels are top targets in terms of the biology, the chemistry for drugging them is really challenging. Ion channels are very large proteins: small-molecule drugs only have a limited interaction surface. This means small molecules generally struggle to target the ion channel sufficiently, and so the side effect profile for ion channel drugs is usually quite bad”, says Steve.
A resurgence in ion channel research
After their initial peak, the interest in ion channels started to decline. However, research into ion channels is still essential to improving healthcare in a range of disease areas. “The need hasn’t gone away. We’ve not solved chronic pain and a lot of other neurological problems (such as motor neurone disease) that have an ion channel basis”, says Steve.
Now, new technology is reviving interest in ion channel research. One of the main advances supporting drug discovery in this area is automation. Patch clamp systems mean that plate-based assays are now commonplace, allowing researchers to investigate 384 experiments at a time. This ability for high throughput screening has accelerated ion channel research, by opening bigger compound libraries for investigation.
Despite these technological breakthroughs, using small-molecule drugs as hits simply wasn’t working for targeting ion channels. However, developments elsewhere in drug discovery found researchers focusing on biologics as treatments. In recent years, peptides have become hot leads for drug discovery, with many pharmaceutical companies dedicating resources and research efforts to this area. Initially researchers investigated antibodies but have more recently focused on smaller peptides with small-molecule-like properties.
Uniting research into biologics with ion channel targets changed the game. Peptides such as those found in tarantula venom can be selective at targeting ion channels. Although ion channel drugs from venoms are still in their infancy, there are 11 venom-derived drugs available on the market, including Captopril: the first ever anti-hypertensive. However, it’s not just venom that can target ion channels, and new advances in other chemistries are also being investigated to modulate these difficult targets.
The long and short of peptides is that they make excellent therapeutics for targeting ion channels. Longer peptide-based structures can be more effective than small molecules at targeting the ion channel owing to their bigger scaffold, offering promising new avenues to explore in drug development.
Exploring wider channels
Alongside advances in technology and biologics, research in this area is growing as ion channels are being identified elsewhere as potential targets. Genome-wide association studies determined that some ion channels were involved in disease but not major operation of the body, such as cardiac pacing or brain function, meaning they could be ideal targets for other therapeutic areas such as oncology.
“People are talking about ion channels in places we didn’t expect them to be important – one of those is cancer. Ion channels in cancer is a very new field”, Steve says. This importance is because cells not only control their voltage for how they communicate with each other, but they also affect the structural conformation of proteins on the surface. For example, inflammatory white blood cells have potassium channels on them – opening potential new treatment options for conditions such as autoimmune diseases.
As well as oncology, ion channel research can benefit other therapeutic areas like neurological disorders and epilepsy. With so many potential therapeutic areas to be tackled by targeting ion channels, researchers are only beginning to scratch the surface of what can be achieved.
Ion channels: a hot topic
Ion channels are challenging targets. However, they are critical in understanding and treating many diseases. “As we start to go into these new disease areas where ion channels weren’t thought to be involved, there’s a lot of untapped opportunity”, Steve says.
New technologies such as automated patch clamp systems are making research easier and reinvigorating the crucial field. However, ground-breaking advancements in ion channel research can’t be achieved without collaboration and sharing knowledge. It’s imperative that scientists come together to discuss the developments, challenges, and opportunities in this vital area.
The ELRIG drug discovery hot topic workshop on ion channels on 16 March 2022 is a networking event addressing the new challenges for patient benefit. Held at the historic global Discovery Park in Sandwich, the free event highlights key developments in ion channel research as well as the challenges and opportunities. Learn more about the latest in ion channel research by registering for the hot topic workshop on ion channels.
