Modes of action

Virus replication involves multiple stages, and   each stage (attachment and penetration, uncoating of the nucleic acid, transcription and trans- lation, genome replication, and release of mature progeny) can be a target for antiviral drug intervention, as illustrated for HIV in Figure. To date, the most common target is viral nucleic acid metabolism by compounds known as nucleoside analogs or non- nucleoside inhibitors. Many of the first antivirals targeted against HIV acted against the viral polymerase (reverse transcriptase) such as azidothymidine (AZT) and lamivudine (also effective against HBV). A range of antivirals are  effective towards different stages of the  influenza virus  replication cycle such as amantidine, which blocks  uncoating by blocking the  ion  channel that forms by the  viral M2 protein; ribavarin, which inhibits the  viral  RNA polymerase; and  zanamivir, which prevents the  final  egress  of the  virus by inhibiting neuraminidase activity. Many viruses produce a virus-specific protease to process their proteins and this has been a valuable target for drug inhibition against HIV (e.g. ritonavir, saquinavir). A series of inhibitors of Picornaviridae act by directly binding to the virion capsid, blocking the interaction among the virion and the receptor on the cell surface that facilitates penetration and uncoating.

Perhaps the most successful antiviral compound is the nucleoside analog acyclovir (ACV– now named aciclovir and sold under the trade name Zovirax), with more than 40 million patients treated. The drug inhibits the replication of HSV and has been administered prophylactically with no ill effects for over 20 years to individuals to suppress recurrences of genital herpes. ACV is an analog of the natural nucleoside guanosine and in this form is inactive and harmless to cells. Activation requires three enzymatic phosphorylation steps, to the active drug molecule ACV triphosphate. The HSV thymidine kinase enzyme can convert ACV to ACV monophosphate (ACV-MP), but ACV is a poor substrate for cellular enzymes, which do not perform this step. Hence ACV remains inactive in uninfected cells. By contrast, the  conversion of ACV to ACV-MP in HSV-infected cells is rapidly followed by conversion to the triphosphate (ACV-TP) form  through the action of cellular enzymes and  it then enters the nucleotide pool within these cells. ACV-TP competes with guanosine triphosphate as a substrate for HSV DNA polymerase (cellular DNA polymerases are much less sensitive) and as the ACV-TP is linked into the growing chain of replicating viral DNA it forms a chain terminator. There is no 3’-OH group on the ACV sugar moiety to link with the next nucleotide residue and hence the growing chain of virus DNA can extend no further, terminating virus replication. Table 1 highlights the modes of action of a range of antiviral compounds.

Interferon is a natural human product (a cytokine) that acts on the surface of normal cells to render them immune to virus replication. The compound is used to treat hepatitis B and C infections (usually accompanied by ribavirin) but is toxic, the side effects mimicking the symptoms of influenza. A newer version, polyethylene glycol interferon (Pegin- terferon; Roche), is less toxic and more stable, allowing a reduced dosing regime of one subcutaneous injection per week, rather than three.