In light of the recent spread of monkeypox virus, now declared a public health emergency of international concern by the World Health Organization, there is a need for treatments. In an article published in Clinical Infectious Diseases, authors review three antiviral agents with activity against monkeypox: cidofovir, brincidofovir, and tecovirimat.
Human monkeypox, caused by the monkeypox virus, a member of the genus Orthopoxvirus within the Poxviridae family of double-stranded DNA (dsDNA) viruses, was first described in a baby in the Democratic Republic of Congo in 1970. Since then, it has resulted in multiple outbreaks in Central and West Africa, and occasionally in Europe and North America. Human-to-human transmission in households has been reported, especially among those unvaccinated against smallpox.
Cidofovir
Although cidofovir has broad activity against many DNA viruses including orthopoxviruses, it is only FDA approved for the treatment of cytomegalovirus retinitis. Cidofovir (CDV) is a prodrug, which must first enter host cells, where it is converted into the active form, CDV diphosphate (CDV-pp). CDV-pp has a prolonged intracellular half-life, and slows viral DNA replication by being incorporated into the growing DNA strand. Pharmokinetics suggest poor oral absorption and is available as intravenous infusions.
In humans, CDV has been used to treat ocular cowpox and as a topical treatment for molluscum cantiogosum.
Brincidofovir
Brincidofovir (BCV) is a lipid-conjugated CDV analogue, FDA-approved in 2021 for the treatment of smallpox. Like CDV, BCV has broad activity against dsDNA viruses. It can be be taken up by the small intestines, and unlike CDV, which slowly crosses cellular membranes, brincidofovir readily enters host cells due to its lipophilicity. Inside cells, BCV is converted into CDV and then CDV-pp. CDV-pp reaches higher intracellular concentrations after BCV administration due to its ability to cross cellular membranes more efficiently. Like CDV, BCV has a prolonged intracellular half-life and inhibits viral replication.
In prairie dog models, which exhibit similarity to the human course, BCV improved survival when administered shortly after infection, suggesting that early treatment is important.
Tecovirimat
Tecovirimat was FDA approved in 2018 for the treatment of smallpox, and has activity against orthopoxviruses, but has no notable activity against other dsDNA viruses. Tecovirimat targets a gene which encodes for membrane protein p37, responsible for the formation of extracellular enveloped virus.
The oral route results in better absorption for tecovirimat, and is effective against monkeypox virus in macaques and prairie dogs. Administration within 72 hours of exposure to poxvirus reduced lesion severity and mortality in various animal models.
Tecovirimat synergises with BCV, and was successfully used to treat monkeypox in two human cases.
Conclusion
The authors note that while CDV and BCV inhibit DNA replication, tecovirimat is more specific to orthopoxviruses and prevents enveloped virus formation, stalling cell-cell transmission.
BCV and tecovirimat could be promising therapeutic candidates based on their tolerability profiles, they conclude. More studies are needed to identify those most at risk from monkeypox and establish the optimal initiation time and duration for therapy.
