Opioid medications are highly effective for pain relief but come with serious risks. Their side effects include dizziness and even life-threatening respiratory issues. The misuse of these substances leads to around half a million fatalities globally each year. Researchers at the University of Geneva (UNIGE) have identified a molecule named nanobody NbE, which attaches firmly and persistently to cell receptors that typically interact with opioids, effectively hindering the drugs’ effects. Furthermore, they have developed even smaller molecules that possess the same characteristics, potentially offering more effective solutions than existing treatments to lessen the adverse effects associated with opioids. These findings are detailed in the journal Nature Communications.
Opioids represent a broad category of medications, including substances like morphine, fentanyl, and tramadol. While these potent drugs are primarily used for pain relief, they also create feelings of euphoria by affecting brain nerve cells. However, their high potential for addiction and severe side effects make them dangerous. Misused, both natural and synthetic opioids have emerged as the most lethal substances in the United States and the growing crisis is now posing a threat to Europe as well.
“There is an urgent need to create new molecules that can better manage the side effects for patients and address the risks of opioid overdoses,” states Miriam Stoeber, an associate professor in the Department of Cell Physiology and Metabolism at UNIGE Faculty of Medicine, who led and coordinated the project. “To understand how a molecule functions, it’s essential to know its impact on brain cells. In our research, we utilized tiny natural proteins derived from llama antibodies, known as nanobodies, designed to specifically bind to the target receptor on the cell surface.”
The remarkable binding strength of nanobody NbE
Researchers at UNIGE have identified that NbE, one of the nanobodies they studied, can bind extremely tightly and persistently to opioid receptors, preventing opioids from attaching to these receptors and thus blocking their effects. “To explore how NbE interacts with its target, we employed advanced structural biology techniques at the new Dubochet Centre for Imaging,” explains Andreas Boland, an assistant professor in the Department of Molecular and Cellular Biology at UNIGE Faculty of Science, and co-last author of the research. “We discovered a unique binding mechanism in which only a small segment of the nanobody is responsible for its precise receptor selectivity. Understanding which part of the nanobody plays this key role allows us to devise new approaches to achieve similar effects using pharmaceuticals.”
Smaller molecules, significant benefits
Although nanobodies are much smaller than traditional antibodies, they are still relatively large. Their production can be expensive, and they might not effectively reach their intended targets in the body. In collaboration with Professor Steven Ballet’s team from the University of Brussels, the UNIGE researchers created a set of even smaller molecules in the lab that replicate the key segment of NbE responsible for its selective binding to opioid receptors. “By effectively blocking opioid receptors, our newly developed molecules hold the potential to reverse or diminish the harmful side effects of opioids. In cases of overdose, they could offer a more effective and longer-lasting option than naloxone, which is currently used. We will now work on refining their structure to enhance their efficacy and improve their delivery to targeted nerve cells in the brain,” Stoeber concludes.
