Youwen Zhang

Chronic pain affects 20-40% of adults worldwide, and opioid analgesics have become one of the primary means of pain treatment. While traditional opioid painkillers provide therapeutic effects, they also come with serious side effects, including respiratory depression and addiction, which greatly limit their clinical use. Zhuang Youwen is dedicated to studying the molecular mechanisms regulating opioid receptor activity and signal transduction, aiming to provide new insights for the rational design and discovery of novel opioid analgesics with high efficacy and low toxicity.

Youwen was the first to reveal the precise structures of morphine and fentanyl binding to the μ-opioid receptor (μOR), clarifying the long-standing confusion in opioid receptor research field regarding the binding modes of morphine and fentanyl. He also elucidated the structure-activity relationship of numerous fentanyl derivatives with μOR, providing templates for the future design of safer opioid analgesics. Furthermore, he discovered that different drug molecules can activate μOR to produce multiple receptor conformations and active states. He then revealed the molecular mechanisms by which ligands mediate biased signaling through μOR, proposing new mechanisms for promoting G protein bias, thus paving the way for the rational design and evolution of G protein-biased μOR drugs.

He systematically explained the mechanism by which endogenous opioid peptides selectively recognize and activate opioid receptors, proposing that opioid receptors follow a conserved activation mechanism. He also identified several new potential druggable pockets in opioid receptors, which will effectively promote the development of novel opioid drugs.

Youwen’s in-depth research into the molecular mechanisms regulating opioid receptor activity and signal transduction has resolved multiple long-standing issues in the field of opioid receptor pharmacology. His research findings not only enhance the understanding of the biological and pharmacological properties of opioid receptors but also clarifies the underlying logic for designing and developing novel opioid drugs, thus guiding the discovery of next-generation opioid medications​.