Scientists unlock keys to fight Monkeypox

A new study reveals the molecular mechanisms behind the key enzymes that Monkeypox virus needs to replicate, thus providing new hope for dealing with this emerging global health threat.

Researchers from a multinational team led by Chinese scientists successfully mapped the three-dimensional structure of Monkeypox “core protease”, a basic viral protein that acts like molecular scissors to process other viral proteins needed for the virus to mature.

“This represents a catalytically favorable state and provides new insights into substrate binding patterns,” the research team noted in their study, detailing how they determine not only the structure of the enzyme, but how it can determine its interaction with potential inhibitors.

The significance of this discovery is in the context of a re-explosion of MPOX outbreak. In August 2024, the World Health Organization announced the international public health emergency concern caused by the spread of MPOX clade IB MPXV in the Democratic Republic of the Congo and other African countries. This marks the second emergency in two years, with more than 133,000 countries worldwide having cases since 2022.

Current prevention and treatment options remain limited. “Vaccine developed for smallpox prevention cannot provide comprehensive protection against MPXV,” the researchers noted. “Recent data suggest that antiviral tecovirimat fails to reduce the duration of MPOX lesions compared to placebo.”

This breakthrough in this research may change that. The team not only mapped the structure of the enzyme, but also designed inhibitors of the peptide based on its findings. These customized design molecules effectively inhibit viral proteases in laboratory tests, showing promising activity against montoxy and ionoformin viruses.

Scientists have used advanced imaging techniques including cryo-electron microscopy and X-ray crystallography to visualize enzymes at near-atomic resolution. What they found was unexpected—when two identical protein molecules paired, the core protease formed a unique “dance companion” fold.

What is even more fascinating is the discovery that enzymes change shape when they bind to their target. “These changes gracefully demonstrate how CorePro transitions from an unfavorable state in Apo-enzyme to a catalyzing a favorable state in complex structures,” the researchers explained.

The most promising inhibitor compounds exhibited nanomolar efficacy in enzyme assays and had no significant toxicity to the activity of live viruses in cell culture. This shows that they can form the basis for developing much-needed new therapies.

Since the orthotopic viruses like Monkeypox pose an increasingly serious threat to global health, especially since smallpox vaccinations mostly cease, this study provides promising avenues for effective antiviral drugs that can help curb future outbreaks.

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