(Vienna, December 6, 2023) People with chronic pain are often dependent on medications from the opioid group, some of which have significant side effects. In this sense, the search for alternatives has been the focus of science for a long time. As part of an international study led by MedUni Vienna, an opioid-like active ingredient was developed which, as demonstrated in animal models, can effectively relieve pain but results in significantly fewer undesirable side effects. Researchers have developed a computer-aided method that has enormous potential to improve the search for active ingredients and therefore drug therapies for other diseases. The study was recently published in the renowned journal Nature Communications.
Given that active ingredients from the opioid group that are often used in pain medications can lead to drug addiction with serious consequences, including respiratory paralysis, the research team led by first author Edin Muratspahić and study leader Christian Gruber of Institute of Pharmacology at MedUni Vienna focused on developing new opportunities in drug discovery. Opioid analgesics, such as fentanyl or morphine, act mainly on the so-called µ-opioid receptor in the brain, which is associated with serious side effects. That’s why researchers from Austria, Australia and the US set out to find drug candidates that bind to a related receptor, the so-called κ-opioid receptor, another important target for regulating pain in the human body.
New avenues for drug development
In order to specifically design chemical compounds that have a high binding affinity to their drug target, researchers used a new computer-aided design process. This de novo design, as the method is called, has now been applied to the family of G protein-coupled receptors (abbreviated GPCR). These are considered the most important drug targets in pharmacology, as approximately one third of all drugs act on these cellular receptors. Using the combination of de novo design, pharmacological and structural analyses, only four compounds had to be synthesized and experimentally characterized to finally identify a promising molecule: DNCP-β-NalA(1) (“De novo circular peptide-β-naloxamine”). .As studies have shown, this recently developed opioid-like active ingredient had a strong pain-relieving effect in animal models, without triggering accompanying symptoms such as sedation or depressive mood. Through targeted activation of individual κ-receptor cellular signaling pathways -Opioid active ingredient promises better tolerability while reducing side effects.
“As part of our study, we developed a process that searches for active ingredients and
-development, e.g. B. of new painkillers could revolutionize”, says study leader Christian Gruber, emphasizing the scope of the research work. The de novo design represents a huge improvement over drug discovery methods previously used in pharmaceutical research, such as virtual molecule library simulations or high-throughput molecule-based screens. Furthermore the process opens up the prospect of finding better active ingredients for other G protein-coupled receptors in order to develop medicines for the treatment of e.g. B. cardiovascular, metabolic or mental diseases can develop with fewer side effects. The potential of currently discovered active ingredient candidates for drug therapy of pain will now be examined and confirmed in additional studies. “Even though it will still be a few years before they are used in clinical practice, our discovery should give hope to many patients suffering from chronic pain,” says Gruber.
Publication: Nature Communications
Design and structural validation of peptide-drug conjugate ligands of the kappa-opioid receptor;
Edin Muratspahić, Kristine Deibler, Jianming Han, Nataša Tomašević, Kirtikumar B.
Jadhav, Aina-Leonor Olivé-Marti, Nadine Hochrainer, Roland Hellinger, Johannes Koehbach,
Jonathan F. Fay, Mohammad Homaidur Rahman, Lamees Hegazy, Timothy Craven, Balazs R.
Varga, Gaurav Bhardwaj, Kevin Appourchaux, Susruta Majumdar, Markus Muttenthaler,
Parisa Hosseinzadeh, David J. Craik, Mariana Spetea, Tao Che, David Baker, Christian
W. Gruber;
https://doi.org/10.1038/s41467-023-43718-w