Chinese scholar Cell's latest article: another step towards making better opioids

In the ongoing effort to improve opioid painkillers, Chinese scientists have used cryoEM technology to solve the detailed structure
of the entire family of opioid receptors binding to their natural peptides.
Structure-guided biochemical studies were subsequently conducted to better understand the mechanisms
of peptide receptor selectivity and signaling drugs.

The work, published in the journal Cell, provides a comprehensive structural framework that should help drug developers rationally design safer drugs to relieve severe pain
.
It was completed by the team of researcher Xu Huaqiang/associate researcher Zhuang Youwen, together with the team of researcher Xie Xin and Professor Wang Mingwei
.

Opioids relieve pain by mimicking the pain
relief functions that occur naturally in our neurological symptoms.
They are our best and strongest painkillers
.
Unfortunately, they have side effects such as numbness, addiction, and respiratory depression that lead to overdose deaths
.

For years, scientists have been trying to overcome the problem of side effects in a variety of ways, all involving one or more of the four opioid receptors, but to no avail
.
What scientists continue to explore is the creation of peptides or peptide-inspired small molecule drugs
.

Peptides are short chains of amino acids, and you can think of them as short proteins
.
Certain naturally occurring or endogenous polypeptides bind to opioid receptors on the cell surface to produce analgesic effects, also known as pain relief
.
We can think of analgesics as anesthetics, except that they do not "shut down" nerves to numb the body or change consciousness
.
So, the idea is to create a peptide drug that has a strong analgesic effect without numbing nerves or altering consciousness, or causing digestion, breathing or addiction problems
.

Using cryo-electron microscopy (cryoEM) and a series of cellular biomechanical experiments, the researchers systematically resolved the detailed structure
of endogenous peptides that bind to all four opioid receptors.
These structures reveal details
of how specific native opioid peptides selectively recognize and activate opioid receptors.
The researchers also used exogenous peptides or drug-like compounds in some experiments to understand how they activate receptors
.

The cryoEM structure of agonist binding receptors with their G protein effector complexes (called "active states") represents what these receptors look like when signaled in the cell, providing a detailed view of
peptide receptor interactions.
The researchers used the structure to guide the design of mutant receptors and then tested these receptors in biochemical analysis in cells to determine how they altered receptor signaling
.
Understanding these interactions can be used to design drugs that are selective for opioid receptor subtypes, as well as to produce certain signal transduction outcomes
that may be more beneficial than traditional opioids.

Previous studies have shown that the structure of the opioid receptor is in an inactive or active state, and the active state structure is only present in the mu-opioid receptor subtype, which is the main target of drugs such as fentanyl and morphine
.
In the Cell paper, the authors show the complex of an agonist-binding receptor with its G protein effector, which is achieved by cryoEM technology
.

Medications such as OxyContin, oxycodone, and morphine can have a variety of effects within cells and throughout neurological symptoms, including pain
relief.
But they also have an effect on the digestive and respiratory systems and interact with cells leading to addiction
.
Fentanyl, meanwhile, is another powerful painkiller, but the way it binds to opioid receptors can cause serious side effects, including a shutdown
of the respiratory system.

The idea behind this study is to find the mechanistic cause
of the effectiveness of pain relief without triggering the cellular mechanisms that lead to serious side effects and overdose.