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The methyl group in thymidine has been replaced by an iodine atom 12.3.1 Nucleoside analogues Antiviral therapy is aimed at preventing viral DNA from being replicated within the host cell. The strategy is to use molecules which resemble natural nucleosides but which are modified to make them nonfunctional. These are called mucleoside analogues. Idoxuridine HOCH If you would like to remind yourself about the structure of DNA and the functioning of these agents then you should refer to the RECAP section at the end of this chapter. An example of a nucleoside analogue is shown in Figure 12.2. Here, the natural nucleoside is thymidine Figure 12.2 The close relationship between the nucleoside analogue idoxuridine and the natural compound thymidine. 106 Essential microbiology for pharmacy and pharmaceutical science • it causes adverse effects to kidney, bone marrow and so aciclovir is not phosphorylated and remains inactive. liver; See Figure 12.3. . it cannot kill latent viruses - it only prevents Points to note about the uses of aciclovir are as replication; follows: • it has now been superseded by other less toxic drugs. . It is used in the treatment of herpes infections of the In the search for less toxic nucleoside analogues, skin and mucous membranes: aciclovir was developed. Aciclovir is a substituted gua - herpes simplex virus types I and II; nine derivative that lacks an-OH group at position 3 on - herpes simplex keratitis; the sugar so it cannot accommodate chain elongation. - varicella zoster (chicken pox and shingles). Aciclovir itself is inactive and it must be phosphorylated . It can be given orally, topically, or by intravenous to form the nucleoside triphosphate in order to be infusion. utilized by DNA polymerase. • Its solubility is poor, hence it should not be given by In virus infected cells aciclovir is phosphorylated by bolus injection - it is infused slowly over 1 hour. the viral enzyme thymidine kinase to form aciclovir . The pH of the solution is high (11) and may lead to monophosphate. Subsequent phosphorylation to di irritation at the site of infusion. and tri- phosphates is carried out by cellular kinases. Poor solubility leads to poor absorption by mouth so In noninfected cells thymidine kinase does not exist and high doses are needed:

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In the treatment of herpes simplex virus type 1, an analogue of nucleoside is first phosphorylated by thymidine kinase, to the monophosphate. Cellular kinases phosphorylates the monophosphate to make the diphosphate. It is then phosphorylated to triphosphate so that ot can be in it's active form.