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Following the discovery of the first effective antiviral compound (idoxuridine) in 1959, nucleoside analogues, especially acyclovir (ACV) for the treatment of herpesvirus infections, have dominated antiviral therapy for several decades. However, ACV and similar acyclic nucleosides suffer from low aqueous solubility and low bioavailability following oral administration. Derivatives of acyclic nucleosides, typically esters, were developed to overcome this problem and valaciclovir, the valine ester of ACV, was among the first of a new series of compounds that were readily metabolized upon oral administration to produce the antiviral nucleoside in vivo, thus increasing the bioavailility by several fold. Concurrently, famciclovir was developed as an oral formulation of penciclovir. These antiviral 'prodrugs' thus established a principle that has led to many successful drugs including both nucleoside and nucleotide analogues for the control of several virus infections, notably those caused by herpes-, retro- and hepatitisviruses. This review will chart the origins and development of the most important of the antiviral prodrugs to date.

Inhibition of varicella-zoster virus (VZV) replication by (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) has been examined in vitro under various experimental conditions. The 50% inhibitory dose (ID50) of BVDU for VZV replication in human embryonal fibroblast (HEF) cultures was 0.016 micrograms/ml, if the assay was based on the reduction of visible foci. If the assay was based on the reduction of immunofluorescent foci, the ID50 was 3 times higher. There was no significant difference in ID50, whether the HEF cultures were infected with cell-free or cell-associated VZV. When the HEF cells were infected with VZV at different multiplicities of infection (MOI), the ID50 of BVDU increased in parallel with the increase of MOI. BVDU was normally added immediately after virus infection. However, the addition of BVDU could be delayed until 8 hr after infection without substantial decrease of activity. On the other hand, BVDU did not cause any inhibition of focus formation when it was removed within 8 hr after VZV infection. If removed at 24 or 48 hr after infection, BVDU caused a significant reduction in focus formation. BVDU had no effect on focus formation if added to the HEF cells before virus infection. BVDU was also found to inhibit VZV focus formation in Vero cells, but only at an ID50 that was 5-10 times higher than the ID50 noted in HEF cells.

This article describes several approaches to a selective therapy of virus infections: (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU [brivudin]) for the therapy of herpes simplex virus type 1 and varicella-zoster virus infections: (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC [cidofovir]) for the therapy of various DNA virus (i.e., herpesvirus, adenovirus, papillomavirus, polyomavirus, and poxvirus) infections; 9-(2-phosphonylmethoxyethyl)adenine (PMEA [adefovir]) for the therapy of retrovirus, hepadnavirus, and herpesvirus infections; (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) for the therapy and prophylaxis of retrovirus and hepadnavirus infections; and nonnucleoside reverse transcriptase inhibitors (NNRTIs), such as tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(IH)-one and -thione (TIBO), 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), alpha-anilinophenylacetamide (alpha-APA), and 2',5'bis-O-(tert-butyldimethylsilyl)-3'-spiro-5"-(4"-amino-1",2"-oxat hiole- 2",2"-dioxide)pyrimidine (TSAO) derivatives, and thiocarboxanilides for the treatment of human immunodeficiency virus type 1 (HIV-1) infections. For the clinical use of NNRTIs, some guidelines have been elaborated, such as starting treatment with combinations of different compounds at sufficiently high concentrations to effect a pronounced and sustained suppression of the virus. Despite the diversity of the compounds described here and the different viruses at which they are targeted, they have a number of characteristics in common. As they interact with specific viral proteins, the compounds achieve a selective inhibition of the replication of the virus, which, in turn, should be able to develop resistance to the compounds. However, as has been established for the NNRTIs, the problem of viral resistance may be overcome if the compounds are used from the start at sufficiently high doses, which could be reduced if different compounds are combined. For HIV infections, drug treatment regimens should be aimed at reducing the viral load to such an extent that the risk for progression to AIDS will be minimized, if not avoided entirely. This may result in a real "cure" of the disease but not necessarily of the virus infection, and in this sense, HIV disease may be reduced to a dormant infection, reminiscent of the latent herpesvirus infections. Should virus replication resume after a certain time, the armamentarium of effective anti-HIV and anti-herpesvirus compounds now available, if applied at the appropriate dosage regimens, should make the virus return to its dormant state before it has any chance to damage the host. It is unlikely that this strategy would eradicate the virus and thus "cure" the viral infection, but it definitely qualifies as a cure of the disease.

At the 25th International Conference on Antiviral Research, I received a special recognition for my contribution to the International Society of Antiviral Research over a period of 25 years (from 1987 until 2012). This review follows the theme of my presentation at that event, which comprised 10 reminiscences, all with a Japanese connection concerning the success, or otherwise, in the clinical development of: double- and single-stranded polynucleotides; suramin, a polysulfonate; dextran sulfate, a polysulfate; brivudin; BVaraU; 2',3'-dideoxynucleoside analogues; HEPT; adefovir and tenofovir; CXCR4 antagonists; and elvitegravir.