Led by graduate student Jeff DiBerto, the 黑料网 lab of Bryan Roth teamed with scientists in China to publish detailed structures of the entire human opioid receptor family to guide the creation of more targeted pain medications.
CHAPEL HILL, NC 鈥� In the continuing effort to improve upon opioid pain relievers, American and Chinese scientists used cryoEM technology to solve the detailed structures of the entire family of opioid receptors bound to their naturally occurring peptides. Subsequent structure-guided biochemical studies were then performed to better understand the mechanisms of peptide-receptor selectivity and signaling drugs.
This work,聽, provides a comprehensive structural framework that should help drug developers rationally design safer drugs to relieve severe pain.
This work was spearheaded by the lab of Eric Xu, PhD, at the CAS Key Lab of Receptor Research in China, in collaboration with the lab of Bryan L. Roth, MD, PhD, at the 黑料网, where graduate student Jeff DiBerto led the pharmacological experiments to understand the receptors鈥� signaling mechanisms.
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.
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 鈥渢urn off鈥� 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.
鈥淭he problem in the field is we鈥檝e lacked the molecular understanding of the interplay between opioid peptides and their receptors,鈥� said Roth, co-senior author and the Michael Hooker Distinguished Professor of Pharmacology. 鈥淲e鈥檝e needed this understanding in order to try to rationally design potent and safe peptide or peptide-inspired drugs.鈥�
鈥淭his 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,鈥� said DiBerto, first author and PhD candidate in the Roth lab. 鈥淲e provide more needed information to keep pushing the field forward, to answer basic science questions we hadn鈥檛 been able to answer before now.鈥�
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.
鈥淲e are attempting to build a better kind of opioid,鈥� Roth says, 鈥淲e鈥檙e 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.鈥�
Co-first authors of the Cell paper are Yue Wang and Youwen Zhuang of the CAS Key Laboratory of Receptor Research and the State Key Laboratory of Drug Research at the Shanghai Institute of Materia Medica in the Chinese Academy of Sciences. Other authors are Edward Zhou and Karsten Melcher of the Van Andel Research Institute in Grand Rapids, MI, Gavin Schmitz and Manish Jain at the 黑料网, and Qingning Yuan, Weiyi Liu, and Yi Jiant at the CAS Key Laboratory.
The above is excerpted from the original article published on 黑料网 Health and 黑料网 Newsroom, by Mark Derewicz, January 12, 2023.
Brian Roth and his lab are members of the 黑料网 Pharmacology Department. Jeff DiBerto is a graduate student in the Pharmacology Graduate Program.