Antiviral Activity Spectrum and Target of Action of Different Classes of Nucleoside Analogues

Abstract

Depending on the target enzyme with which they interact, nucleoside analogues exhibit marked differences in their antiviral activity spectrum. The activity spectrum of those nucleoside analogues that interact with cellular enzymes involved in the biosynthesis of the RNA and DNA precursor nucleotides encompasses virtually all RNA and DNA viruses. In contrast, the activity spectrum of those nucleoside analogues that are targeted at a specific viral enzyme will be limited to those specific virus types whose enzyme(s) they interact with. For a given compound, the antiviral activity spectrum can often be predicted from identification of the target enzyme, and, vice versa, the mode of action can be deduced from the activity spectrum.¹ This concordance between antiviral activity spectrum and mode (target) of antiviral action will be scrutinized for the following categories of nucleoside analogues: AKAR analogues (i.e. ribavirin) that are targeted at IMP dehydrogenase; carbocyclic adenosine analogues (i.e. neplanocin A) that are targeted at AdoHcy hydrolase; OMP decarboxylase inhibitors such as pyrazofurin; CTP synthetase inhibitors such as cyclopentenylcytosine; acyclic guanosine analogues (i.e. acyclovir, ganciclovir) which act as viral DNA chain terminators following initial phosphorylation by the virus-encoded thymidine kinase (TK) or protein kinase; thymidine analogues (ie. BVDU) whose antiviral action (at the viral DNA polymerase level) also depends on a preferential phosphorylation by the viral TK; acyclic nucleoside phosphonates which can be divided into different subcategories depending on whether their activity spectrum includes all major DNA viruses (herpes, adeno, pox, papova and hepadna, or herpes-, hepadna-, and retroviruses, or only hepadna- and retroviruses); 2′,3′-dideoxynucleoside analogues which, following phosphorylation to the 5′-triphosphate form by cellular enzymes, act as chain terminators of the retro- and hepadnaviral reverse transcriptase; and certain nucleoside derivatives (i.e. HEPT, TSAO) which act as highly specific inhibitors of the reverse transcriptase of human immunodeficiency virus type 1 (HIV-1) (Table 1).