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▎WuXi AppTec content team editor
of innovative analgesic drugs targeting μOR based on the concept of G protein bias.
" The research team noted
.
On November 10, 2022, Cell, a top academic journal, published an important result
from a Chinese research team online in the form of a long article.
The cooperation of Xu Huaqiang/Zhuang Youwen, Xie Xin's team and Wang Mingwei's team from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences revealed for the first time the mechanism of action of powerful analgesics fentanyl and morphine to recognize and activate μ opioid receptors (μOR), and systematically explored and deepened the understanding and understanding
of the mechanism of μOR signaling regulation.
This achievement will lay an important foundation for promoting the development of new opioid analgesic drugs with high efficiency and low toxicity.
Professor Huaqiang Xu and Professor Xin Xie, who led the study, were winners of the WuXi AppTec Life Chemistry Research Award in 2016 and 2012
, respectively.
Opioids are currently the most widely used and highly effective analgesics
.
Human use of opioids dates back thousands of years to the use of plant opium poppy for analgesic and sedative and recreational purposes
.
Subsequent studies found that the opioid morphine was the main substance
that exerted activity in the poppy.
Common opioids include natural opioid alkaloids such as morphine and cocaine, and synthetic opioids such as
demeraldine and fentanyl.
Although these opioids have a strong analgesic effect, their toxic side effects are also well known
.
The most worrisome side effect is "high addiction," and respiratory depression caused by drug addiction can lead to death
.
These toxic side effects undoubtedly greatly limit the clinical use
of opioid analgesics.
To design and develop new opioid analgesics that are safer and more effective, a thorough understanding of the molecular mechanisms by which opioid analgesics interact with their target molecules, opioid receptors, is key to
breaking the game.
Image source: 123RF
Classic opioid analgesics such as morphine and fentanyl work by
activating μ opioid receptors.
As a class of G protein-coupled receptors, opioid receptors are activated and mainly transmit signals through two different types of molecules: GI/O proteins and β-arrestin
.
Some previous studies suggest that the analgesic effects of opioids are mediated by the G protein signaling pathway of μOR, while the side effects are caused by the β-arrestin signaling pathway
.
However, several recent studies have questioned this hypothesis, arguing that neurotoxic side effects such as respiratory depression are not
related to arrestin signaling.
Despite doubts, a lot of research has been invested in the development of μOR agonist drugs with G protein pathway bias
.
In 2020, the US FDA approved the first and so far only μOR analgesic designed based on the concept of G protein bias, Oliceridine (TRV130), for the treatment
of moderate to severe pain.
The drug exhibits lower toxic side effects
than morphine.
of innovative analgesic drugs targeting μOR based on the concept of G protein bias.
" The research team noted
.
▲The analgesic effects and side effects of opioids may be related to the pathway selection of opioid receptors (Image source: Reference [1])
In this study, scientists first used cryo-EM technology to obtain human μOR binding to equilibrium agonists such as fentanyl, morphine, and DAMGO (showing bidirectional signaling activity of G protein and inhibitory protein), as well as high-resolution three-dimensional structures of G protein biased agonists such as TRV130, SR17018, and PZM21, and then characterized the signaling characteristics of μOR under the activation of different signaling active agonists by molecular dynamics simulation and cellular-level functional analysis
。
Structural information showed that fentanyl occupies an additional binding pocket at the transmembrane region of μOR TM2 to TM3 near the outer end of the cell compared to morphine; In addition, fentanyl's aniline ring side chain forms a direct π-π hydrophobic interaction
with amino acid residues W295 and Y328.
These characteristics confer 50-100 times higher receptor-activating activity
on fentanyl than morphine.
▲The three-dimensional structure of human μOR combined with opioids such as fentanyl and morphine (Image source: Reference [1])
Through the molecular docking and point-mutation function verification of different fentanyl derivatives, the researchers further revealed the structure-activity relationship between fentanyl and its derivatives and the receptor μOR, and revealed the key role
of different degrees of interaction between drug molecules and amino acid residues such as D149, Y150, W135 and W320 in determining the different activities of fentanyl and its derivatives (carfentanil, sufentanyl, oxymetrentanyl, etc.
).
The analysis of the analyzed series of structures and molecular dynamics simulations showed that the G protein biased agonist PZM21 was more inclined to bind to the TM2/3 side of the μOR ligand binding pocket, while the equilibrium agonist fentanyl showed a broader and more balanced interaction with the μOR transmembrane region, and made the intracellular domain of μOR more compact, which was conducive to the binding of μOR to β-arrestin.
It also explains the molecular mechanism by which equilibrium agonists exhibit β-arrestin activity
.
These results provide a breakthrough in identifying key binding characteristics
that mediate the two signaling pathways.
Based on the mechanism provided by structural biology, the researchers also designed and synthesized two novel G protein-biased fentanyl derivatives FBD1 and FBD3 with different activities based on the fentanyl molecular backbone, confirming the idea
of biased key sites.
This mechanism, as well as the efficacy of potential novel opioid receptor modulators, needs to be further verified
in subsequent animal experiments.
▲ The structure of opioids with different chemical structures combined with human μOR (Image source: Reference [1]).
In summary, the new study analyzes the high-resolution three-dimensional structure of opioid analgesic drugs such as fentanyl, morphine, and olisteridine activating μOR, and combines a variety of cellular-level functional analysis and molecular dynamics simulation methods to clarify the structure-activity relationship between fentanyl series derivatives and the drug target μOR, as well as the key structural determinants of μOR-mediated downstream inhibitory protein
signaling.
"This study is the first to resolve a series of near-atomic-resolution structures of agonist morphine and fentanyl binding μOR, clarifies the confusion about fentanyl binding patterns, gives us the first insight into how it interacts with μOR, and provides a precise template
for the design of future painkillers.
" 。 Professor Zhang Xu, academician of the Chinese Academy of Sciences, commented, "This study based on structural and multiple pharmacological function experiments found that weakening the interaction of opioid molecules with the sixth and seventh transmembrane regions of μOR can weaken or even eliminate arrestin signaling and trigger G protein biased signal transduction, which provides new ideas for subsequent design and discovery of opioids with pathway bias, which will promote the discovery
of highly effective and low-addictive analgesics.
" ”
Pei Gang, an academician of the Chinese Academy of Sciences, said that this study makes us "know the truth and know the reason"
of the pathway selection of opioid receptors.
He pointed out: "With the development of structural biology, Chinese researchers not only analyze the structure of biological macromolecules through multidisciplinary means such as biochemistry combined with computers, but also further explore and solve major problems and urgent needs
in the frontier fields of life science and biomedicine from these structures.
The work, published in Cell, is a great example of translational research that not only advances the understanding of the molecular mechanisms of opioids, but also lays the foundation
for structure-based drug design and development.
”
This study was completed by the team of Xu Huaqiang/Zhuang Youwen, Xie Xin and Wang Mingwei of Shanghai Institute of Materia Medica
.
Zhuang Youwen, associate researcher of Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and Wang Yue, He Bingqing and He Xinheng, doctoral students of Shanghai Institute of Materia Medica, are co-first authors
of the paper.
Prof.
Huaqiang Xu, Prof.
Xin Xie, Prof.
Mingwei Wang and Prof.
Youwen Zhuang are co-corresponding authors
.
Also participating in this study are Researcher Cheng Xi, Researcher Yang Dehua, Researcher Jiang Yi, Researcher Jiang Xiangrui, Dr.
Guo Shimeng of Shanghai Institute of Materia Medica, Rao Qidi, a graduate student jointly trained by Shanghai Institute of Materia Medica, Fudan University and ShanghaiTech University, Zhou Qingtong, researcher of the School of Basic Medical Sciences of Fudan University, and Professor Karsten Melcher and Dr.
X.
Edward Zhou of the Wen Anluo Research Institute
.
At the same time, the research work has received strong support and help
from Academician Jiang Hualiang and researcher Shen Jingshan of Shanghai Institute of Materia Medica.
Shanghai Yuansi Biotech provided compound samples
for this study.
The work was supported by the cryo-EM platform of Shanghai Institute of Materia Medica, and the peak EM platform of Shanghai Institute of Materia Medica, and was funded by the National Natural Science Foundation of China, the Key R&D Program of the Ministry of Science and Technology, the Pilot Project of the Chinese Academy of Sciences, the National Science and Technology Major Project (Key Project of New Drug Creation), the Shanghai Science and Technology Major Project, and the Special Assistant Research Project of the Chinese Academy of
Sciences.
Resources:
[1] Zhuang et al.
, Molecular recognition of morphine and fentanyl by the human m-opioid receptor, Cell (2022), https://doi.
org/10.
1016/j.
cell.
2022.
09.
041
