Anti-Herpes Nucleoside Analogues
by eMedExpert staff
Medical references reviewed: August, 2018
Antiviral agents can be categorized as virucidals, antiviral chemotherapeutic agents, and immunomodulators.
Nucleoside analogues are antiviral chemotherapeutic agents, which exhibit their "antiviral effect" primarily while viral replication is active at the host-cell level.
Nucleoside analogues are the major class of antiviral agents used for the management of Herpes Simplex Virus infections. They include acyclovir and penciclovir with their respective prodrugs valacyclovir and famciclovir. Nucleoside analogues are quite similar with respect to their chemical structure.
Herpes antivirals do not eradicate the virus, which is recurrent and lifelong. Antiviral chemotherapy helps by controlling symptoms and signs of herpes infection and shortening the course of outbreaks. When the medications are discontinued, they do not affect the frequency or severity of recurrences.
Anti-herpes medications disrupt the process by which the virus makes copies of itself and spreads to new cells. They work by inhibiting an enzyme that the virus has but human cells do not have and then interrupting the viruses' ability to synthesize DNA.
Nucleoside analogues are highly potent and selective inhibitors of viral enzyme thymidine kinase (TK). They depend on the activity of the viral thymidine kinase to convert the drug to a monophosphate form and subsequently interfere with viral DNA replication.
The principle of antiviral activity of nucleoside analogues acyclovir and penciclovir relies on the fact that herpes viruses (herpes simplex virus, varicella zoster virus and cytomegalovirus) encode their own nucleoside kinases which have much lower substrate specificity than their cellular counterparts. Therefore, they are able to monophosphorylate certain nucleoside analogues whereas cellular nucleoside kinases cannot do so or only to a very limited extent.
The resulting analogue monophosphates are metabolized, by cellular kinases, to the respective triphosphates, which show distinctly lower molar inhibitory constants (Ki values) for herpes virus-encoded DNA polymerases than for cellular DNA polymerases. This step of antiviral selectivity causes obligate chain termination in the case of acyclovir and, thus, cessation of virus production. On the other hand, in contrast to acyclovir, which has only one hydroxyl group in its acyclic "sugar" moiety, penciclovir possess two hydroxyl groups and can be internally incorporated into the growing DNA chain. Its mode of antiviral action is less well understood so far.
Acyclovir, a synthetic acyclic guanosine analog, was seen as the start of a new era in antiviral therapy. It is a prototypical antiviral agent. Acyclovir itself is polar, and thus the oral bioavailability is low.
The pharmacologically active form of the compound is ACV-triphosphate. It is highly potent and has specific activity against herpes simplex virus types 1 and 2.
Acyclovir undergoes monophosphorylation (adds one phosphate group) catalyzed by a virus-encoded enzyme thymidine kinase. The formation of the monophosphate can only take place in the presence of the virus, thus the drug accumulates as the monophosphate only in infected cells. It is then converted to a diphosphate and triphosphate by “normal” host enzymes in the cell. ACV-triphosphate inhibits the viral DNA polymerase from incorporating guanosine triphosphate and is itself incorporated. The DNA cannot grow further, add more groups and the chain terminates.
The mechanism of action is thus twofold: inhibition of viral DNA polymerase and chain termination of DNA once it has been incorporated into the nucleic acid.
Acyclovir is most active against herpes simplex viruses types 1 and 2; activity against varicella zoster virus (VZV) also is substantial but approximately ten-fold less. Epstein Barr virus (EBV) is only moderately susceptible because EBV has minimal thymidine kinase activity. Activity against Cytomegalovirus (CMV) is poor because CMV does not have a unique thymidine kinase, and so CMV DNA polymerase is poorly inhibited by acyclovir triphosphate.
Mechanism of resistance: Resistant strains of HSV have mutations in either the viral thymidine kinase gene or the viral DNA polymerase. Resistance occurs when mutations of the viral thymidine kinase result in an enzyme which no longer phosphorylates acyclovir. Or when the viral DNA polymerase mutates to a form that no longer recognizes the activated drug.
Therefore, viral mutants exhibit cross-resistance to other antiviral agents that require thymidine kinase activation, such as famciclovir, ganciclovir, and valacyclovir. Acyclovir-resistant HSV strains that exhibit thymidine kinase deficiency are also resistant to famciclovir and penciclovir.
Valacyclovir is a valine ester of acyclovir. It was designed to enhance oral bioavailability of the parent compound. The prodrug is converted to acyclovir in the intestine and liver. It has an oral bioavailability three to five times greater than that of acyclovir, higher plasma concentration, and longer half life.
Valacyclovir has the same mechanism of action, antiviral spectrum, and resistance profiles as those of its parent compound.
Valacyclovir is active against herpes simplex viruses types 1 and 2, varicella zoster virus, and Epstein-Barr virus. Cytomegalovirus, which does not encode thymidine kinase, is resistant at clinically achievable oral doses.
Famciclovir is the inactive diacetyl ester prodrug of penciclovir, an acyclic nucleoside analog of guanosine. Famciclovir is rapidly converted to its active form, penciclovir by deacetylation and oxidation.
The parent compound, penciclovir, has virtually no oral bioavailability (less than 5%). In contrast, famciclovir has a very high bioavailability of 77%.
Penciclovir is phosphorylated more efficiently than acyclovir in HSV- and VZV-infected cells. It has similar mechanism of action except that it is not an obligate chain terminator.
Penciclovir is converted to its triphosphate form (penciclovir triphosphate), which selectively inhibits viral DNA polymerase by competing with deoxyguanosine triphosphate. It is 100 fold less potent in inhibiting DNA polymerase than acyclovir, but is present in higher concentration and for prolonged periods in infected cells.
Penciclovir is active against members of the herpes virus family, with greatest activity against HSV-1, somewhat lower activity against HSV-2, and less activity against VZV. CMV is relatively resistant, and EBV has intermediate susceptibility.
Mechanism of resistance: Penciclovir-resistant strains occur when mutations produce deficient or altered thymidine kinase or altered DNA polymerase. However, some acyclovir-resistant strains may remain sensitive to penciclovir.
Ganciclovir is a nucleoside analogue that differs from acyclovir by having an extra hydroxymethyl group on the acyclic side chain. Its active form is ganciclovir triphosphate, which is an inhibitor of viral rather than cellular DNA polymerase. However, ganciclovir is more toxic to human cells than is acyclovir.
Intracellular ganciclovir is phosphorylated to the phosphate derivative by virus-encoded enzymes. Cellular enzymes further convert it to diphosphate and triphosphate form. Ganciclovir triphosphate is a competitive inhibitor of viral DNA polymerases. Incorporation of ganciclovir triphosphate into viral DNA causes a slowing and subsequent cessation of viral DNA chain elongation.
Ganciclovir has greatest activity is against CMV, although it is active against other herpes viruses. Ganciclovir is also active against HSV and against some mutants resistant to acyclovir.
- 1. The Merck Manual of Medical Information. Mark H. Beers et al., eds. 2nd Home Edition. Whitehouse Station, NJ: Merck; 2003.
- 2. Physicians' Desk Reference. 59th ed. Montvale, N.J.: Thomson PDR, 2005.
- 3. Arvin A, Campadelli-Fiume G, Mocarski E, et al. Human Herpesviruses Biology, Therapy, and Immunoprophylaxis. Chapter 64: Antiviral therapy of HSV-1 and -2.
- 4. Bacon TH, Levin MJ, Leary JJ, Sarisky RT, Sutton D. Herpes simplex virus resistance to acyclovir and penciclovir after two decades of antiviral therapy. Clin Microbiol Rev. 2003 Jan;16(1):114-28.
Published: May 05, 2007
Last updated: February 04, 2017