New aminoadamantane derivatives as inhibitors of F13 envelope protein from mpox virus.

Mpox is a zoonotic viral disease caused by monkeypox virus (MPV), currently classified as a public health emergency of international concern by the WHO. In this study, Aminoadamantane (AMA) and five synthetic derivatives were evaluated as potential candidates for treating mpox. The compounds exhibited remarkable in vitro activity against MPV. The selectivity index (SI) values exceeded 1500, indicating a high degree of antiviral potency, particularly 3F2 (SI > 37,878.79). Regarding the mechanism of action, all compounds tested acted at specific steps of the viral replication cycle. Derivative 3F2, which reduced the viral titers up to 100 times (IC50=0.0264), seems to interfere with the intracellular steps of the replication cycle. Transmission electron microscopy further revealed a conspicuous and significant decrease in the number of mature MPV viral particles induced by 3F2, which indicates the ability of this compound to interfere in viral particle assembly. Additionally, putative molecular target identification suggested 3F2 has the MPV F13 phospholipase as a possible target. Docking analysis on the modeled MPV F13 suggested a higher affinity of 3F2 in comparison to AMA, and equivalent to the positive control tecovirimat. A synergistic assay involving 3F2 and tecovirimat supported this finding, as no synergy was observed between 3F2 and tecovirimat, suggesting a common molecular target. All in all, AMA and especially 3F2 show robust activity against MPV, positioning them as promising options for antiviral therapeutic development vis-à-vis the emergency state of Mpox around the globe.