Scientists plan to develop new types of analgesic drugs to help deal with the "o

Opioid analgesics are currently one of the most effective options for treating moderate to severe pain. Statistics show that nearly 20%-40% of adults worldwide are troubled by chronic pain such as cancer pain, back pain, and myofascial pain. The drug targets of opioid analgesics are opioid receptors, including mu, kappa, delta opioid receptors, and nociceptin receptors (NOPR). At present, most of the marketed opioid analgesics are agonists of the mu-type opioid receptor (muOR). However, these drugs, while exerting strong analgesic effects, are also accompanied by serious side effects such as respiratory depression and addiction, which greatly limit their clinical application. Every year, the abuse of opioid drugs causes more than 100,000 deaths, among which fentanyl and its derivatives are the main causes of the "opioid crisis." Therefore, the development of new opioid analgesics with high efficiency and low toxicity is urgent.

Zhuang Youwen, a researcher at the School of Basic Medical Sciences of Shanghai Jiao Tong University, is committed to in-depth research on the activity and signal transduction regulatory molecular mechanisms of opioid receptors and has made important progress. His research not only deepens the understanding of the biological and pharmacological characteristics of opioid receptors but also points the way for the development of new generations of opioid drugs.

By clarifying the mechanism of action between opioid drugs and receptors from multiple aspects, he has provided an accurate template and innovative approach for the design of safer new opioid analgesics, helping to address the global spread of the "opioid crisis." Zhuang Youwen has become one of the Chinese candidates for the "35 Innovators Under 35" in the 2023 MIT Technology Review.

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Switching to GPCR halfway, he has published many top journals.In January 2018, the team of Professor Eva Nogales, a member of the National Academy of Sciences and a renowned structural biologist, published an important research achievement in Science. They used cryo-electron microscopy technology to resolve the molecular structure of the important anticancer drug target—Polycomb Repressive Complex 2 (PRC2) holoenzyme. This research coincided with Zhuang Youwen's doctoral thesis. At that time, there was only one year left before his doctoral graduation. Faced with this challenge, Zhuang Youwen experienced a period of confusion and hesitation. Under the encouragement and guidance of his mentor, Professor Xu Huaqiang, he decisively turned to the field of G protein-coupled receptor (GPCR) research.

GPCR plays a key role in cellular signal transduction and is currently the largest family of membrane proteins targeted by drugs. To date, nearly more than 130 types of GPCR targets have been used for clinical drug development, with about 34% of marketed drugs targeting GPCRs. In-depth understanding of the activity and signal transduction mechanism of GPCRs, especially revealing their molecular mechanisms at the atomic level and conducting pharmacological research, is of great significance for the design and development of GPCR-targeted drugs.

Subsequently, Zhuang Youwen applied for and received funding from the Chinese Academy of Sciences to go to the famous Van Andel Institute in the United States for international joint training as a doctoral student. He undertook two research projects, respectively, the structure and function of the N-formyl peptide receptor 2 (FPR2) and the cannabinoid receptor 2 (CB2) and their signal protein complexes. Zhuang Youwen's study in the United States not only broadened his academic horizons and improved his research capabilities but also led to outstanding scientific achievements. The relevant results were published in the journals Nature Communications and Cell.

After completing his doctorate, Zhuang Youwen chose to stay at the Shanghai Institute of Materia Medica to work, focusing on the study of neurotransmitter GPCR receptors, such as opioid receptors, dopamine receptors, and cannabinoid receptors. "Looking back, the twists and turns encountered during my doctorate actually became a turning point in my scientific research path. It was the interest and persistence in scientific research, as well as the encouragement of my mentor, that became my greatest motivation to keep moving forward," Zhuang Youwen said.

In recent years, Zhuang Youwen has made a series of breakthroughs in his research. His research not only answered many long-standing scientific questions in various fields but also provided new directions and guidance for the development of new drugs targeting neurological diseases. These achievements have also been highly recognized and evaluated in the field, published in top journals such as Cell and Cell Research, and selected as the cover of Cell and the best paper of the year by Cell.Currently, I am fully committed to guiding the design and development of new highly effective and low-toxicity drugs targeting neurological diseases with these achievements, aiming for industrial transformation. We have collaborated with numerous laboratories at home and abroad to explore emerging technologies such as large-scale molecular virtual library screening and intelligent drug design, to carry out rational drug molecule design and discovery.

Zhuang Youwen revealed this.

Focusing on the development of new opioid drugs to address the opioid crisis.

One of Zhuang Youwen's research goals is to develop new opioid drugs that have potent analgesic effects with minimal side effects.

Opioid receptors belong to the G protein-coupled receptor (GPCR) family, and their activated signals can be transmitted through G protein or β-arrestin pathways. For a long time, researchers believed that the G protein pathway mainly mediates analgesic effects, while the β-arrestin pathway is associated with side effects such as gastrointestinal dysfunction, respiratory depression, and tolerance. The idea of developing G protein signal-biased drugs has become a strategy for the development of new opioid drugs. Although some research results in recent years do not conform to this view. Under the guidance of this concept, in 2020, the U.S. FDA approved the first G protein-biased designed μ opioid receptor (μOR) analgesic drug Oliceridine (TRV130) for the treatment of moderate to severe pain. This drug shows lower toxic side effects than morphine, but still needs a "black box warning" to indicate its potential risks.

However, due to insufficient understanding of the molecular mechanism of G protein preference for μOR, over the past 20 years, G protein-biased agonists for μOR have mainly been obtained through large-scale high-throughput blind screening, which greatly hinders the rational design and discovery of new G protein-biased analgesic drugs targeting μOR.In November 2022, Zhuang Youwen, as the first author and co-corresponding author, published a groundbreaking study in Cell, which for the first time revealed the mechanism of action between the μ-opioid receptor (μOR) and clinically common opioids such as morphine and fentanyl, as well as the important regulatory mechanisms by which drug molecules mediate signal bias transmission of μOR. This research not only clarified the confusion in the field regarding the binding mode of fentanyl but also provided a theoretical basis for the design of new low-toxicity opioid analgesics.

Based on insights provided by structural biology, pharmacology, and computational biology data, Zhuang Youwen and his collaborative team made precise modifications to fentanyl, synthesizing two derivatives, FBD1 and FBD3, with G protein pathway preference, further validating the concept of key sites for preference.

Following this, in January 2023, Zhuang Youwen and his collaborators published a "sister paper" research article in Cell again, systematically exploring the action patterns of the endogenous endorphin system and opioid receptors, elucidating the selective and conserved mechanisms within, unlocking the effect switch of the pain-relieving secret contained in the human body itself, which will effectively promote the development of new peptide-based analgesic drugs.

Looking to the future, Zhuang Youwen plans to take the opioid receptor as one of the main research objects, delving into the study of its signal regulatory mechanism and the pharmacological mechanism of opioid analgesics. He will use an interdisciplinary approach to explore the molecular mechanisms of signal preference transmission, allosteric regulation, and oligomer formation of opioid receptors. At the same time, he will collaborate with neurobiologists to explore the neural circuit mechanisms of the respiratory depression, addiction, and constipation caused by opioid drugs, and combine drug molecule design to develop new high-efficiency, low-toxicity opioid analgesics.

In addition to opioid receptors, Zhuang Youwen is also committed to the study of the dopamine receptor system. Dopamine receptors are important targets for the treatment of neurological and mental diseases such as Parkinson's disease and schizophrenia. He and his collaborators have elucidated the ligand selectivity and G protein selectivity molecular basis of representative dopamine receptors D1R and D2R, and discovered the allosteric regulatory sites of D1R. These findings provide important references for the design of new drugs targeting dopamine receptors.Zhuang Youwen stated: "I hope to develop brand-new, safe, and efficient innovative drugs for the treatment of neurological disorders such as Parkinson's disease, depression, and chronic pain by continuously and deeply exploring the regulatory mechanisms of neurotransmitter GPCR signal transduction and the mysteries of the pharmacology of related neuropsychiatric disease treatment drugs, enabling more patients to regain their health and happiness."