Structural and dynamic insights into F13L variations in monkeypox virus and their impact on tecovirimat resistance.

Abstract

The recent global outbreak of Monkeypox virus since 2022, particularly outside Africa, has underscored its significant threat to public health. Genomic surveillance from multiple countries has revealed diverse genetic variations among circulating Monkeypox virus strains. Notably, a common F13L (E353K) mutation was identified in strains responsible for concentrated outbreaks in the United Kingdom and North America. The F13L is the current target of the only approved drug for poxvirus treatment, tecovirimat (previously known as ST-246), Previous studies have reported that the F13L (G277C) mutation significantly increases resistance. However, the impact of the shared F13L (E353K) mutation on viral transmission and its potential role in conferring tecovirimat resistance remains unclear. To address this, we employed homology modeling, molecular docking, and molecular dynamics simulations to investigate the phospholipase activity of the F13L protein. Our findings suggest that resistance to tecovirimat in F13L and its mutants may be attributed to altered flexibility of the drug-binding pocket and changes in the distance between the H334 residue and the fluorine atom in tecovirimat. This study provides a framework for rapidly assessing the resistance of emerging Monkeypox virus variants to tecovirimat and for guiding the rational modification of existing therapeutics to counter new viral threats.