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Area of Science:

  • Virology
  • Structural Biology
  • Drug Discovery

Background:

  • Mpox virus (MPXV) outbreaks are a growing global health concern, necessitating effective antiviral treatments.
  • Tecovirimat is a primary therapeutic agent for mpox, yet its precise mechanism of action and resistance pathways remain incompletely understood.
  • Emergence of tecovirimat-resistant MPXV strains, characterized by mutations in the viral phospholipase F13, poses a significant public health challenge.

Purpose of the Study:

  • To elucidate the molecular mechanism by which tecovirimat exerts its antiviral effect against mpox virus.
  • To determine the structural basis for tecovirimat's interaction with viral phospholipase F13.
  • To investigate the impact of F13 mutations on tecovirimat efficacy and resistance.

Main Methods:

  • X-ray crystallography was employed to determine the structure of the F13 homodimer, both in its apo form and in complex with tecovirimat.
  • Biochemical assays were utilized to assess the drug-induced dimerization of F13 in solution.
  • Cell-based assays were performed to evaluate the effect of tecovirimat and F13 mutations on viral egress and replication.

Main Results:

  • Tecovirimat functions as a molecular glue, inducing the dimerization of the mpox virus phospholipase F13.
  • The crystal structure reveals tecovirimat binding at the F13 homodimer interface.
  • Clinical F13 escape mutations are located at the dimer interface, disrupting tecovirimat-mediated dimerization and conferring drug resistance.
  • Tecovirimat-induced dimerization of F13 was confirmed in both solution and cellular contexts.

Conclusions:

  • Tecovirimat's mode of action involves promoting F13 dimerization, crucial for blocking viral egress.
  • F13 mutations conferring resistance directly interfere with this drug-induced dimerization process.
  • Understanding this mechanism provides a basis for improved monitoring of mpox outbreaks and the development of next-generation antivirals.
  • This research offers insights into designing more potent and resilient therapeutics against poxviruses.