Opioids are a group of strong medications that include morphine, fentanyl, and tramadol. They are mainly used to relieve pain but can also create a feeling of euphoria by affecting brain cells. However, these drugs are highly addictive and can cause serious side effects.
There is an urgent need to develop new molecules to mitigate the side effects for patients and manage the risks of opioid-related overdoses. However, a better understanding of the workings of molecules is needed to determine how they affect the brain cells.
Researchers at the University of Geneva (UNIGE) have found a molecule called nanobody NbE that attaches strongly to opioid cell receptors, blocking their effects. They also created even smaller molecules with the same properties, which could be much more effective in reducing the harmful effects of opioids.
Scientists used tiny natural proteins derived from llama antibodies, called nanobodies, designed to bind specifically to the target receptor on the cell’s surface.
Nbe- one of the nanobodies under study, can bind so tightly and durably to specific opioid receptors that it prevents opioids from binding to these same receptors, therefore blocking the drug‘s activity.
Researchers used high-resolution structural biology methods to determine how NbE binds to its target.
Andreas Boland, assistant professor in the Department of Molecular and Cellular Biology at UNIGE Faculty of Science and co-last author of the study, said, “We identified a unique binding mode where only a small portion of the nanobody is responsible for its correct receptor selectivity. Knowing precisely which part of the nanobody is at stake allows us to imagine new ways to induce the same effects with pharmaceuticals.”
Nanobodies are smaller than antibodies but still significant, making them expensive to produce and potentially less effective at reaching target tissues. Working 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 mimic the critical part of NbE, which is responsible for binding to opioid receptors.
Miriam Stoeber said, “By durably blocking opioid receptors, our new molecules have the potential to reverse or reduce the deleterious side effects of opioids. In case of overdose, they could provide a better, longer-lasting option than naloxone, the treatment currently in use. We will now refine their structure to improve even further their efficiency and facilitate their delivery to the targeted nerve cells in the brain.”
Journal Reference:
- Yu, J., Kumar, A., Zhang, X. et al. Structural basis of μ-opioid receptor targeting by a nanobody antagonist. Nat Commun 15, 8687 (2024). DOI: 10.1038/s41467-024-52947-6