Acyclovir Zovirax

Structural Formula u

Ball-and-Stick Model

Year of discovery: 1970s (by Burroughs Wellcome); Year of introduction: 1982; Drug category: Antiviral; Viral DNA synthesis inhibitor; Main uses: For the treatment of herpes infections (e.g., cold sores, genital herpes, chicken pox); Other brand names: Zovir; Related drugs: Valacyclovir (Valtrex), Penciclovir (Denavir), Ganciclovir, Valganciclovir (Vitrasert).

Acyclovir, an acyclic guanine nucleoside analog, was one of the first highly effective systemic antiviral agents in clinical practice. It followed earlier nucleoside antiviral agents such as idoxuridine and ribavirin (see page 149) that were not widely used, o.

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The success of acyclovir demonstrated convincingly that it is possible to find antiviral agents that are relatively nontoxic and selective for the pathogen.

Acyclovir was approved in 1982 for the treatment of infections by various herpes viruses such as genital herpes, cold sores, shingles, and chicken pox. It is unique among the early antiviral agents because it is highly selective for virus infected cells and is minimally cytotoxic. Acyclovir mimics deoxy-guanosine, which is a critical building block for DNA, and differs from deoxyguanosine in the sugar moiety (red) by lacking carbons #2 and #3 (see scheme to the right).

Acyclovir is actually a prodrug that inhibits the replication of viral DNA because it is an excellent substrate for the viral thymidine kinase enzyme (only present in virally infected host cells), but not for the mammalian enzyme.2 In uninfected human cells acyclovir is not phosphorylated. Once inside an infected host cell, acyclovir is first converted to the monophosphate by the viral enzyme and then transformed to acyclovir triphosphate by kinases of the host cell (see scheme). Acyclovir triphosphate is a potent competitive inhibitor of viral DNA polymerase and retards the incorporation of the natural substrate, deoxyguanosine triphosphate, into a growing

DNA chain. However, when phosphorylated acyclovir is attached to viral DNA (highlighted in red below), it causes DNA chain termination because no further lengthening is possible; viral replication stops.

Acyclovir Trihosphate (acyclo-GTP)

Deoxyguanosine Triphosphate (dGTP)

Acyclovir Trihosphate (acyclo-GTP)

Deoxyguanosine Triphosphate (dGTP)

The valine ester derivative of acyclovir, valacyclovir, has the advantage of greater bioavailability (5x) and is now the preferred form.J In addition, there are other effective analogs in clinical use, for example ganciclovir and its valine ester, valganciclovir. These valine esters are hydrolyzed in the body by esterases to the parent drugs.

Valacyclovir (Valtrex ) Valganciclovir (Vitrasert1™1)

1. Antiviral Res. 2006, 71, 134-140; 2. Br. J. Pharmacol. 2006, 147. 1-11; 3. Exp. Rev. Anti-lnfect. Ther. 2006, 4, 367376; Refs. p. 176

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