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Chapter 10 : Antiviral Targets in Orthopoxviruses
Category: Viruses and Viral Pathogenesis; Clinical Microbiology
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This chapter summarizes many targets for orthopoxviruses that might be exploited in the discovery of additional agents for potential diseases and indicates the mechanisms of action of a number of compounds. The viral DNA polymerase performs a critical role in viral replication, and its susceptibility to nucleoside analogs has made it the dominant target for the development of antiviral drugs. The synthesis of deoxynucleotides is also catalyzed by the heterodimeric ribonucleotide reductase encoded by F4L and I4L. Ribonucleotide reductase converts ribonucleotides to the corresponding deoxyribonucleotides at the level of the diphosphate and supplies deoxyribonucleoside triphosphates to support DNA replication in the cytoplasm. A number of small molecules are known to broadly target protein kinases, and it is possible that medicinal chemistry efforts could identify selective inhibitors. Immature virions containing genomic DNA undergo complex maturation that leads to the condensation of virus cores and involves proteolytic events, the loss of D13, and the formation of new disulfide linkage catalyzed by the viral redox system. The complex replication cycle of the orthopoxviruses requires the concerted activities of numerous viral proteins. The chapter also summarizes each of the stages of viral replication, notes the viral proteins that perform critical functions, and identifies specific inhibitors that affect these processes.