The most abundant element on Earth – sodium – might hold the key to allowing scientists to develop opioids or other drugs with far fewer side effects.
In a study published Wednesday by Naturescientists from USC, Washington University in St. Louis, and Stanford University have demonstrated that by chemically binding fentanyl to the sodium pockets that exist in nerve cell receptors, they can block harmful side effects of the drug while reducing pain.
Further study is needed, but the results are promising, not only for drug development, but also for addressing the addiction and overdose crisis in the country. According to the National Institute on Drug Abuse, nearly 70,000 Americans died in 2020 from an opioid overdose — most of them from the synthetic opioid, fentanyl. In the 1990s, the Food and Drug Administration approved the use of fentanyl to relieve severe pain in cancer patients, but it has since made its way onto the streets, worsening the national opioid abuse crisis.
“In its current form, fentanyl is like a weapon of mass destruction,” said Vsevolod Katritch, a computer scientist at the Bridge Institute at the USC Michelson Center for Convergent Bioscience and corresponding author of the study. “Our new collaborative work suggests that we might redesign the drug in a way that converts this frequent overdose killer into a much more benign but still effective painkiller. »
Drugs of all kinds are designed to target certain receptors on nerve cells called GCPRs, or G-coupled protein receptors, which act as signal transmitters. These receptors are like switches that mediate a drug’s intended effect on the brain and body, as well as unintended side effects. In the case of fentanyl, the strongest painkiller of all opioids, patients can become addicted and die of respiratory arrest.
Katritch noted that he and fellow scientists Ray Stevens and Vadim Cherezov of the Bridge Institute and USC Dornsife College of Letters, Arts and Sciences have studied the potential of the sodium mechanism since they first identified it. in adenosine and opioid receptors regarding a decade ago.
Katritch and his collaborators said that although more studies are needed to prove that their less harmful version of fentanyl will work in humans, the results have opened a new door for scientists to potentially improve the safety of painkillers.
“We are desperately looking for ways to maintain the analgesic effects of opioids, while avoiding dangerous side effects such as addiction and respiratory distress that too often lead to death,” said corresponding author Susruta Majumdar of the University. from Washington to St. Louis. “Our research is still in its early stages, but we are excited regarding its potential to lead to safer painkillers. »
Beyond opioid receptors, Katritch noted, this work opens up a new molecular design concept for dozens of other GPCRs where such functional conversion into existing drugs would be desirable.
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