Variola virus and Monkeypox virus (VARV (Variola virus); MPXV (Monkeypox virus))

Variola virus is the causative agent of smallpox, a highly contagious and historically devastating human disease, now officially eradicated as of 1980. Monkeypox virus is an emerging zoonotic orthopoxvirus initially restricted to Central and West Africa but now recognized globally due to outbreaks since 2022. Both viruses are large, enveloped, double-stranded DNA viruses with complex molecular architectures, encoding over 180 proteins, including essential replication enzymes and numerous accessory factors affecting host range and virulence. Smallpox fatality was historically high (30–50%), whereas monkeypox is generally milder (1–10%), although severe cases can occur, particularly with Clade I MPXV. Both viruses can be targeted by antivirals, diagnostic molecular assays, and vaccines. Monkeypox virus and variola virus share considerable structural, genetic, and clinical similarities but differ in host range, transmission dynamics, and epidemiological threat. Therapeutics targeting these viruses usually act by inhibiting viral envelope formation, DNA replication, or modulating host immune pathways, but safety concerns persist—especially regarding resistance, immunocompromised hosts, and unpredictable outbreak risk.

Other names

Smallpox virus (Variola virus)Mpox virus, MPXV (Monkeypox virus)Human poxvirus (non-specific)Orthopoxvirus (family/genus level; not specific)

Inhibition of viral envelope formation (e.g., tecovirimat targets VP37 protein); Inhibition of viral DNA polymerase (cidofovir, brincidofovir); Immunomodulation (vaccinia immune globulin); Blocking host signaling pathways to reduce viral replication (MTOR, CHUK/IKBKB, splicing factor kinase inhibitors for MPXV); Induction of protective immunity (smallpox vaccine)