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Poxviruses, including the Variola virus (smallpox) and Monkeypox virus, are unique among DNA viruses because they replicate entirely within the host cell's cytoplasm [Moss, 2013]. This cytoplasmic lifestyle necessitates that the virus encodes its own complete mRNA synthesis machinery, as it cannot utilize the host's nuclear transcription enzymes [Grimm et al., 2021]. The core of this machinery is a large, multi-subunit DNA-dependent RNA polymerase (vRNAP) that is structurally related to eukaryotic RNA polymerase II but functions independently [Grimm et al., 2021]. In addition to the polymerase, the machinery includes essential enzymes for mRNA processing, such as the capping enzyme (D1/D12) and the poly(A) polymerase (E1/J3), which are required to produce stable, translatable viral transcripts [Shuman, 2001]. Because these viral enzymes are distinct from their human counterparts, they represent highly specific targets for antiviral intervention [De Clercq, 2001]. Inhibiting the poxvirus mRNA synthesis machinery can effectively halt the viral life cycle by preventing the expression of early, intermediate, and late genes, thereby blocking genome replication and the assembly of new infectious particles [Byrd & Hruby, 2006].
Inhibition of viral DNA-dependent RNA polymerase activity, disruption of mRNA capping, or interference with transcription termination and polyadenylation [De Clercq, 2001; Byrd & Hruby, 2006].
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