Study explains why tecovirimat fails against some mpox strains

A virus originally found in animals, mpox – which causes the disease of the same name – is now circulating in humans. Since 2022, it has been the cause of major epidemics spreading outside endemic areas in Central and West Africa. Two hundred and fifteen cases of mpox infection were reported to Santé publique France in 2024. Tecovirimat is the drug most commonly used to treat patients infected with the mpox virus. Unfortunately, it is sometimes ineffective against certain variants of the virus that have mutations in an enzyme. Scientists at the Institut Pasteur have been studying this resistance, and have been able to describe more precisely how this enzyme interacts with tecovirimat. This research will make it possible to develop novel antiviral therapeutic approaches. The study was published on February 12, 2025 in Nature Microbiology.

In view of the surge in mpox virus infections in the Democratic Republic of Congo and several neighboring countries over the last few months, and the emergence of a new, possibly more contagious viral strain, in mid-August 2024 the World Health Organization (WHO) declared a public health emergency of international concern for the second time since 2022. In France, the National Authority for Health has updated its vaccination recommendations for those most at risk.

Mpox presents like a mild form of smallpox, with fewer symptoms and a lower case fatality rate (the number of deaths as a proportion of the number of people infected). The disease begins with a fever (myalgia, headaches, fatigue, etc.) followed by rashes over the entire body. Two hundred and fifteen cases of mpox infection were reported to Santé publique France in 2024. So far this year, since January 1, 2025, 10 cases of mpox have been reported. Tecovirimat, which is used as a first-line treatment, has the advantage of being well tolerated. It blocks the spread of viral particles in the body, although its mechanism of action is not yet fully understood. Moreover, this drug is sometimes ineffective against certain strains of the virus which acquire a resistance mutation. This resistance is emerging regardless of the virus clade. In the United States in 2022, around 1% of patients treated with tecovirimat developed drug resistance.

The Structural Biology of Infectious Diseases Unit at the Institut Pasteur has studied how tecovirimat blocks the exit of viruses belonging to the poxvirus family, including the mpox virus, from infected cells. To do this, the scientists used biochemical and computer methods. "The aim was to gain a better understanding of why certain viral variants are resistant to treatment," explains Pablo Guardado-Calvo, Head of the Institut Pasteur's Structural Biology of Infectious Diseases Unit and last author of the study.

Previously, it had been observed that treatment-resistant mpox variants all had mutations in phospholipase F13, a key enzyme in the formation of the viral particle's outer envelope. The hypothesis was therefore that tecovirimat interacts with the F13 enzyme to block infection, which is impossible when the F13 enzyme is mutated. "We therefore analyzed the structure of phospholipase F13, which enabled us to pinpoint the interactions between the drug and the enzyme," explains Pablo Guardado-Calvo. "We have shown that tecovirimat acts as a kind of glue that binds two F13 phospholipases together, preventing it from fulfilling its role in spreading viral particles," he says.

This basic research has enabled us to explain the drug's mechanism of action, and to understand why variants carrying these mutations render antiviral treatment ineffective. "There are still many mysteries surrounding the action of tecovirimat, but our study is a first step. This understanding is essential for the development of new therapeutic approaches effective across all mpox strains," concludes Pablo Guardado-Calvo. Using these structural data, researchers at the Institut Pasteur have just started work on the development of new antivirals.