An Insight into the Replication Mechanism of Smallpox and Monkeypox Viruses

Poxviruses are a family of large, enveloped DNA viruses that infect large numbers of vertebrates and invertebrates, causing severe disease. Some prominent members of the family, viz. variola virus (causative agent of smallpox), and monkeypox (mpox) virus (causes human mpox) are of great concern globally. The crucial enzyme, viz. the DNA polymerase (pol) involved in the multiplication of these viruses in human cells, is studied and found that it shows striking similarities to most of the DNA pols already reported from prokaryotes and eukaryotes and their pol domain uses the same catalytic amino acids in their active sites as reported for other DNA pols. For example, the smallpox and mpox viralcatalytic amino acids in their pol catalytic core regions are the same, viz. -MQ^-4YTYK¹IIANSVY⁸GLM- and-MQ^-4YTYK¹IVANSVY⁸GLM-, respectively and are also the same as that of the host enzymes, viz. the human replicative δ and ε DNA pols, viz. -RQ^-4LALK¹VSANSVY⁸GFT- and –LQ^-4LAHK¹CILNSFY⁸GYV-, respectively. Furthermore, the poxviral proofreading (PR) exonuclease domain is made up of the same active site amino acids as in other DNA/RNA pols, including the host replicative DNA pols, and belongs to DEDD(Y) superfamily of PR exonucleases. In spite of their active site similarities, the smallpox and mpox viral replicative DNA pols showed only 23.75 and 23.69 per cent identities, respectively, to the human replicative δ pol. In contrast, the regulatory zinc-binding motifs (ZBMs) which are typically found in human and other eukaryotic replicative pols (α, δ, ε) at their C-terminal domains (CTDs) are absent in these poxviral DNA pols, but a HNH type homing endonuclease motif, which is identified in the poxviral pols, is absent in humans and other eukaryotic replicative pols. Presently approved vaccines and antivirals for smallpox and mpox are also discussed.