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A research team led by Prof. Ben Ko Chi-bun, Associate Professor of the PolyU Department of Applied Biology and Chemical Technology, has discovered the critical mechanism of action of tetrandrine, a compound derived from Chinese medicine Stephania tetrandra. Their work opens the door to innovative treatments for viral infections and neurodegenerative disorders like Alzheimer's and Parkinson's.

The findings have been in Nature Communications in a paper titled "Tetrandrine regulates NAADP-mediated calcium signaling through a LIMP-2-dependent and sphingosine-mediated mechanism."

Leveraging a specially designed photoaffinity probe alongside other advanced tools to visualize tetrandrine's cellular target, the team found that tetrandrine can target LIMP-2 to alter lysosomal calcium release.

Tetrandrine, a compound isolated from the root of a traditional Chinese medicine (TCM) Stephania tetrandra, has shown promise in combating Ebola virus infection in previous studies. Its precise mechanism of action, however, had remained unclear.

Researchers from The Hong Kong Polytechnic University (PolyU) have discovered that tetrandrine works by blocking the transport of sphingosine鈥攁 lipid molecule essential for cellular signaling鈥攁nd inhibiting the calcium channels. Their research has revealed the critical mechanism of tetrandrine for the first time, opening new avenues for drug discovery and disease treatment.

Tetrandrine is known for its potent antiviral, anti-inflammatory and anti-cancer properties. It has been shown to inhibit nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated calcium efflux, thereby suppressing the activity of the Ebola virus.

Scientists have long believed that tetrandrine elicits its pharmacological activity by directly blocking calcium channels and their release of calcium, which is a key regulator of cellular function and physiology including immune response, metabolism, brain and neuron functions, and viral replication.

They discovered that, instead of directly targeting the calcium channels, tetrandrine binds to the lysosomal integral membrane protein type-2 (LIMP-2) on the lysosome鈥攖he metabolic hub of the cell鈥攁nd blocks the discharge of sphingosine from it.

The team further found that it is the amount of cellular sphingosine that controls the activity of calcium channels: the less sphingosine released, the less calcium that can enter the cells.

With this discovery, the researchers propose that tetrandrine can be used to disrupt processes critical to the survival and replication of viruses, such as Ebola and COVID-19, by targeting LIMP-2 to alter lysosomal calcium release.

Importantly, these findings highlight lysosome-related mechanisms as a new frontier for drug discovery, offering novel strategies for treating diseases caused by calcium imbalance, including neurodegenerative disorders like Alzheimer's and Parkinson's, as well as certain metastatic cancers.

Prof. Ko said, "This is the first time a function of LIMP-2 in calcium signaling has been uncovered. From a cell biology perspective, our study has revealed a completely new pathway for NAADP-regulated calcium signaling, through LIMP-2 and sphingosine. From an anti-viral treatment perspective, the study has identified LIMP-2 as a key target of tetrandrine for the treatment of Ebola virus infection, with broader applications in other antiviral therapies."

While illuminating tetrandrine's biological mechanism, the research team has developed a technology platform that combines photoaffinity probe and multi-omics analysis. This platform not only facilitates studies of natural product biology, but also enables researchers to identify the molecular targets of other natural compounds, particularly those derived from TCM.

By integrating modern analytical techniques with TCM, it modernizes the use of natural products and expands their therapeutic potential in the fight against the most challenging diseases, supporting the development of innovative drugs.

The research redefines how natural compounds, such as tetrandrine, can be applied in modern therapeutic strategies.