Article Dans Une Revue Nature Microbiology Année : 2025

Structural insights into tecovirimat antiviral activity and poxvirus resistance

Olivier Schwartz

Résumé

Mpox is a zoonotic disease endemic to Central and West Africa. Since 2022, two human-adapted monkeypox virus (MPXV) strains have caused large outbreaks outside these regions. Tecovirimat is the most widely used drug to treat mpox. It blocks viral egress by targeting the viral phospholipase F13; however, the structural details are unknown, and mutations in the F13 gene can result in resistance against tecovirimat, raising public health concerns. Here we report the structure of an F13 homodimer using X-ray crystallography, both alone (2.1 Å) and in complex with tecovirimat (2.6 Å). Combined with molecular dynamics simulations and dimerization assays, we show that tecovirimat acts as a molecular glue that promotes dimerization of the phospholipase. Tecovirimat resistance mutations identified in clinical MPXV isolates map to the F13 dimer interface and prevent drug-induced dimerization in solution and in cells. These findings explain how tecovirimat works, allow for better monitoring of resistant MPXV strains and pave the way for developing more potent and resilient therapeutics.
Fichier principal
Vignette du fichier
s41564-025-01936-6.pdf (16) Télécharger le fichier
Origine Publication financée par une institution
licence
DOI

Est documentée par 10.5281/zenodo.14096216

Dates et versions

hal-04947704 , version 1 (14-02-2025)

Licence

Identifiants

Citer

Riccardo Vernuccio, Alejandro Martínez León, Chetan Poojari, Julian Buchrieser, Christopher Selverian, et al.. Structural insights into tecovirimat antiviral activity and poxvirus resistance. Nature Microbiology, In press, ⟨10.1038/s41564-025-01936-6⟩. ⟨hal-04947704⟩
0 Consultations
0 Téléchargements

Altmetric

Partager

More