Scientists unlock weak spot of monkeypox virus, paving way for new drugs

Monkeypox, caused by the monkeypox virus—a close cousin of smallpox—has spread rapidly worldwide. From 2022 to 2025, more than 133,000 cases were reported across 131 countries. In August 2024, the World Health Organization declared monkeypox a global health emergency due to a new strain’s outbreak in Africa. Current vaccines offer limited protection, leaving the world in urgent need of better solutions.

To infect people, the monkeypox virus relies on a tool called core protease (CorePro), which works like a pair of scissors. This tool cuts large protein blocks inside the virus into smaller pieces, like shaping raw materials into parts. These smaller pieces form the viruss shell and core, allowing it to assemble into a complete virus that can invade human cells and multiply.

If the scissors stop working, the virus becomes a pile of useless parts, unable to infect. Scientists identified these scissors as the viruss weak spot—stopping them could halt the virus in its tracks.

Led by teams from multiple institutions with ShanghaiTech University as the first affiliation, a research reveals the cleavage mechanism of the CorePro, offering a clear path to developing new drugs to fight the monkeypox virus. The study is published in Nature.

Using X-ray crystallography and cryo-EM, the team captured the first detailed picture of the CorePro. They found its made of two protein molecules, like dance partners holding hands. These two parts support each other, making the scissors more stable and precise when cutting.

To defeat the virus, the team tested a drug called aloxistatin, originally used for muscle diseases. Aloxistatin acts like a cap, covering the scissors blades so proteins cant get in, stopping the cutting process. While it slowed the virus in lab tests, its effect was moderate.

The real breakthrough came when the team designed six new chemical locks based on the scissors picture. Data in this study shows these new drugs are 10 to 20 times more effective than aloxistatin. These drugs stick to the scissors’ blades like glue, greatly boosting their ability to stop the virus.

They work not only against monkeypox but could also tackle related viruses like smallpox, offering hope for future treatments. This is crucial for controlling monkeypox outbreaks and even preparing for potential smallpox resurgences.

The new drugs are a promising first step. Scientists are now refining them to be safer and more effective, aiming to bring them to patients soon, strengthening global health defenses.

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