A group of scientists collaborated to release comprehensive structures of the entire human opioid receptor family, with the aim of facilitating the development of more precise pain medications.
In an ongoing endeavor to enhance opioid pain medications, scientists from the United States and China utilized cryoEM technology to determine the comprehensive structures of the entire family of opioid receptors when bound to their natural peptides. Further structure-informed biochemical studies were conducted to gain a deeper comprehension of the peptide-receptor selectivity and drug signaling mechanisms.
The findings, published in the journal Cell, offer a comprehensive structural framework that should assist drug developers in creating safer drugs for the alleviation of severe pain.
Opioid drugs relieve pain by mimicking a naturally occurring pain-relief function within our nervous symptoms. They are the best, strongest pain relievers we have. Unfortunately, they come with side effects, some severe such as numbness, addiction, and respiratory depression, leading to overdose deaths.
Alignment of peptide-bound opioid receptors reveals structural features, such as steric effects, that contribute to the subtype-selective binding and functional outcomes observed in biochemical assays. Credit: Roth Lab, UNC School of Medicine
Scientists have been trying for many years to overcome the side-effect problem in various ways, all involving one or more of four opioid receptors to no avail. One way scientists continue to explore is the creation of peptide or peptide-inspired small molecule drugs.
Peptides are short chains of amino acids; think of them as short proteins. Certain naturally occurring, or endogenous, peptides bind to opioid receptors on the surface of cells to create an analgesic effect, also known as pain relief. Think of an analgesic like an anesthetic, except that analgesics do not “turn off” the nerves to numb the body or alter consciousness. So, the idea is to create a peptide drug that has a strong analgesic effect, without numbing nerves or altering consciousness, or causing digestive, respiratory, or addiction issues.
“The problem in the field is we’ve lacked the molecular understanding of the interplay between opioid peptides and their receptors,” said Roth, co-senior author and the Michael Hooker Distinguished Professor of Pharmacology. “We’ve needed this understanding in order to try to rationally design potent and safe peptide or peptide-inspired drugs.”
Using cryogenic electron microscopy, or cryoEM, and a battery of biomechanistic experiments in cells, the Xu and Roth labs systematically solved the detailed structures of endogenous peptides bound to all four opioid receptors. These structures revealed details and insights into how specific naturally occurring opioid peptides selectively recognize and activate opioid receptors. The researchers also used exogenous peptides, or drug-like compounds, in some of their experiments to learn how they activate the receptors.
The cryoEM structures of agonist-bound receptors in complex with their G protein effectors (called their “active state”) represent what these receptors look like when they are signaling in cells, giving a detailed view of peptide-receptor interactions. The Roth lab used the structures solved by the Xu lab to guide the design of mutant receptors and then tested these receptors in biochemical assays in cells to determine how they alter receptor signaling. Understanding these interactions can then be used to design drugs that are selective for opioid receptor subtypes, as well as to produce certain signaling outcomes that may be more beneficial than those of conventional opioids.
“This collaboration revealed conserved, or shared, mechanisms of activation and recognition of all four opioid receptors, as well as differences in peptide recognition that can be exploited for creating subtype-selective drugs,” said DiBerto, first author and Ph.D. candidate in the Roth lab. “We provide more needed information to keep pushing the field forward, to answer basic science questions we hadn’t been able to answer before now.”
Previous research showed the structure of opioid receptors in their inactive or active-like states, with active state structures only existing for the mu-opioid receptor subtype, the primary target of drugs like fentanyl and morphine. In the Cell paper, the authors show agonist-bound receptors in complex with their G protein effectors, made possible through cryoEM technology that did not exist when currently used medications were being developed.
Drugs such as oxycontin, oxycodone, and morphine cause various effects inside cells and throughout the nervous symptom, including pain relief. But they have effects in the digestive and respiratory systems, too, and interact with cells to lead to addiction. Fentanyl, meanwhile, is another powerful pain reliever, but it binds to opioid receptors in such a way as to cause severe side effects, including the shutdown of the respiratory system.
The thrust behind such research led by Xu and Roth is to home in on the mechanistic reasons for pain relief potency without triggering the cellular mechanisms that lead to severe side effects and overdosing.
“We are attempting to build a better kind of opioid,” Roth says, “We’re never going to get there without these kind of basic molecular insights, wherein we can see why pain is relieved and why side effects occur.”
![](https://www.nanoappsmedical.com/wp-content/uploads/2017/05/spacer.jpg)
News
Ethics in Nanomedicine: Key Issues and Principles
Nanomedicine, a branch of nanotechnology, is revolutionizing healthcare by enabling the manipulation of materials at the nanoscale to diagnose, treat, and prevent diseases. Unlike traditional treatments, nanoparticles (NPs) are highly precise in targeting diseased [...]
A call for robust H5N1 influenza preparedness and response
As the global threat of H5N1 influenza looms with outbreaks across species and continents including the U.S., three international vaccine and public health experts say it is time to fully resource and support a [...]
Mucosal COVID-19 boosters outperform mRNA shots in preventing upper airway infections
In a recent study published in Nature Immunology, a team of researchers from the United States used non-human primate models to compare the protection conferred by an intramuscular booster dose of the bivalent messenger ribonucleic acid [...]
How Space Travel Really Changes Astronauts – From the Inside Out
International team reveals previously unknown effects on physiology that could shape the future of long-duration space missions. Researchers have discovered significant changes in the gut microbiome due to spaceflight, which affects host physiology and [...]
Breakthrough in blood stem cell development offers hope for leukemia and bone marrow failure
Melbourne researchers have made a world first breakthrough into creating blood stem cells that closely resemble those in the human body. And the discovery could soon lead to personalized treatments for children with leukemia [...]
Scientists Develop Game-Changing Needle-Free COVID-19 Intranasal Vaccine
A new mucosal COVID-19 vaccine poised to revolutionize the delivery process is especially beneficial for those with a fear of needles. A next-generation COVID-19 mucosal vaccine is set to be a game-changer not only when delivering [...]
Scientists Develop All-in-One Solution To Catch and Destroy “Forever Chemicals”
A new water treatment system developed by UBC researchers efficiently removes and destroys PFAS pollutants using a dual-action catalyst, offering a sustainable and cost-effective solution for water purification challenges. Chemical engineers at the University of [...]
New method accelerates drug discovery from years to months
Researchers from the University of Cincinnati College of Medicine and Cincinnati Children's Hospital have found a new method to increase both speed and success rates in drug discovery. The study, published Aug. 30 in [...]
A new smart mask analyzes your breath to monitor your health
Your breath can give away a lot about you. Each exhalation contains all sorts of compounds, including possible biomarkers for disease or lung conditions, that could give doctors a valuable insight into your health. [...]
Study reveals the role of blood clotting in COVID-19
In a study that reshapes what we know about COVID-19 and its most perplexing symptoms, scientists have discovered that the blood coagulation protein fibrin causes the unusual clotting and inflammation that have become hallmarks [...]
A Novel Cancer Vaccine Combining Nano-11 and ADU-S100
In a recent article published in npj Vaccines, researchers detailed the development of a novel cancer vaccine that combines a plant-derived nanoparticle adjuvant, Nano-11, with a clinically tested STING agonist, ADU-S100. The primary objective was [...]
AI spots cancer and viral infections with nanoscale precision
Researchers have developed an artificial intelligence which can differentiate cancer cells from normal cells, as well as detect the very early stages of viral infection inside cells. The findings, published today in a study [...]
Tiny shards of plastic are increasingly infiltrating our brains, study says
Human brain samples collected at autopsy in early 2024 contained more tiny shards of plastic than samples collected eight years prior, according to a preprint posted online in May. A preprint is a study which has not yet [...]
Scientists Have Discovered Strange DNA in Our Brains – and It Could Be Shortening Our Lives
According to the research, these mitochondrial DNA insertions could be linked to early death. Mitochondria in brain cells frequently insert their DNA into the nucleus, potentially impacting lifespan, as those with more insertions were found to [...]
Watch Out After a Hospital Stay: You Could Be Exposing Your Family to Superbugs
Research indicates hospitals contribute to the local spread of antibiotic-resistant infections. A recent study published in the journal Infection Control & Hospital Epidemiology by the Society for Healthcare Epidemiology of America suggests that family members of [...]
Molecular Trickery: How COVID-19 Silently Sabotages the Human Immune System
Researchers have discovered that SARS-CoV-2 manipulates the human immune system by forcing cells to produce non-functional proteins, hindering the body’s antiviral defenses. This groundbreaking study by teams from prestigious Brazilian universities highlights potential targets for new COVID-19 treatments, [...]