Abdominal pain affects millions, but there are still limited ways to treat it.
University of Queensland (UQ) researchers have built on an emerging body of evidence focused on the peptide hormone oxytocin and its potential for therapeutic pain relief, changing the chemical structure to produce a treatment that won’t be rapidly broken down by gut enzymes before it takes effect. This breakthrough could prove significant, given the challenge of harnessing oral peptides for therapeutics.
“There are two hurdles for producing oral peptide drugs: One, instability against gastrointestinal enzymes/digestion and, two, size restriction to cross the gut-blood barrier,” study lead Markus Muttenthaler, an associate professor from the Institute for Molecular Bioscience at UQ, told New Atlas. “In this work we addressed one, and focused on a drug target in the gut, so we didn’t have to get the peptide drug lead across the gut-blood barrier, which also reduces the chance of any unwanted systemic side effects, making it a safer approach.”
Because of this, pain could be effectively targeted with a pill, bypassing the need for injections. It’s also free of the negative outcomes of current medications such as opioids, which range from constipation, addiction and even narcotic bowel syndrome. To date, the chronic pain associated with gastrointestinal (GI) disorders such as irritable bowel syndrome (IBS) and irritable bowel disease (IBD) has been difficult to treat effectively without also delivering a suite of side-effects.
“Opioids have and are still dominating the pain drug market,” Muttenthaler told New Atlas. “Gut pain is highly prevalent, however, still only a small market compared to all the other pain conditions. Companies are focusing on the next centrally acting painkiller that works for many different pains without side effects. I am just not sure if that is the right approach; I would rather focus on specific types of pain.
“[Gut] pain affects up to 15% of adults in their lifetime, and all we have are anti-inflammatories and opioids which can cause side effects and addiction,” Muttenthaler said. “Our research focuses on peptides that are highly potent and selective molecules and have few side effects. However, nearly all peptide drugs must be injected as they are rapidly digested in the gut.”
Muttenthaler and his team had earlier identified the role that oxytocin could play in treating abdominal pain, but the challenge was to make this peptide-hormone-adjacent molecule resilient enough to withstand the GI tract’s natural metabolism, in order for it to reach its target receptor. A year and three generations of analogs later, and the team had its model compounds.
“We identified the parts of oxytocin that are rapidly broken down by gut enzymes and used medicinal chemistry to render them gut-stable while ensuring that the new molecule was still able to activate the oxytocin receptor,” Muttenthaler said. “We now have a new class of molecules that are potently active but do not degrade in the stomach or intestine, meaning they can be taken orally.”
The oxytocin-adjacent compound also proved to be “potent and fully gut-stable,” successfully reaching its target. It paves the way for a clinical trial.
Oxytocin is perhaps best known as the ‘love hormone’ and the role it plays in helping solidify relationship bonds and triggering reproductive mechanisms such as uterine contractions during childbirth and breastmilk production.
But it’s only recently become a research target surrounding pain relief. The researchers explain that their oxytocin analog is able to make its way through the gut intact to reach the colon, where it takes effect and suppresses pain signals.
“This is a very safe therapeutic approach as it reduces the risk of side effects in the rest of the body, a problem with many other systemic drugs,” Muttenthaler said. “This is an exciting new mode of action to prevent pain.”
Having shown safety and efficacy in this study, the team now hopes to firstly get the drug to pre-clinical trial, as well as work on other, new drug compounds that target the gut.
“We are currently looking for investors to accelerate pre-clinical studies, with the goal of taking it into the clinic,” the lead researcher added, telling New Atlas that if funding wasn’t an issue, the team could have this drug candidate in a Phase I human clinical trial within three years.
The researchers are now looking at more drug discoveries to treat various aspects of IBS, IBD, pain, diabetes and eating disorders, according to Muttenthaler.
“It took a while to establish all the assays and techniques, but now we have the expertise and setup to do this for most peptides,” he says. “This is great as it opens up new avenues of research and we can focus on many other gut drug targets combating gastrointestinal disorders.”
The study was published in the journal Angewandte Chemie.
Source: University of Queensland
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