**3.2. Trisubstituted piperazin-2-one derivative 15D8**

Ying et al. [29] could be a result of slightly elevated cellular thymidine kinase activity, higher in testing in vivo. These authors hypothesize the direct inhibition of the AdV DNA polymerase as

This anti-HIV compound possesses a marked anti-AdV activity, even stronger than cidofovir

Alovudine (FddT) manifest in vitro (IC50 = 0.2–0.7 μg/ml) and in vivo (mouse model of AdV

Anti-AdV activity of these anti-HSV compounds is moderate, and the current data on their

This triazole nucleoside was described initially by Sidwell et al. [35]. Numerous studies were carried out on the mode of action of this compound manifesting activity toward large spectrum of viruses (predominantly RNA containing) belonging to different taxonomic groups. However, there are no data about the mechanism of anti-AdV effect of ribavirin. Several different mechanisms were formulated about the antiviral effects of this compound: (1) decreased levels of intracellular guanosine triphosphate pools based on inhibition of cellular inosine-5-monophosphate dehydrogenase; (2) inhibition of viral polymerases; (3) inhibition of RNA capping activity of viral transcripts; (4) lethal mutagenesis of the viral RNA genomes, also termed "error catastrophe," based on the induction of increased viral mutation rate over the critical error rate (especially expressed on enterovirus replication) via incorporation of the compound into newly synthesized genomes; (5) immunomodulatory role particularly on adaptive immune responses—the compound is inducer of the helper-T-cell type 1 cytokine response, but also a suppressor of the type 2 cytokine phenotype. Data about anti-AdV effect in cell culture experiments are very controversial. It was established that its activity is limited to AdVs of group C and strongly cell culture-dependent [36]. However, the plasma concentra-

a possible mechanism of GCV suppressive effect on AdV DNA synthesis.

pneumonia) anti-AdV activity of the order of that of cidofovir [26, 31].

**2.11. Ribavirin (1-ß-D-ribofuranosyl-1,2,4-triazole-3-carboxamide)**

tions reached by ribavirin are 10 times below the required IC50 value [36, 37].

N′N′-anhydro-bis(β-hydroxy-ethyl)biguanide-HCl (abitylguanide) suppressed markedly the replication of a large spectrum of human AdVs, both standard laboratory strains and strains isolated from epidemic keratoconjunctivitis patients. The magnitude of inhibitory

**2.8. Zalcitabine (2′3'-dideoxycytidine, ddC)**

**2.9. Alovudine**

18 Adenoviruses

in ocular AdV infections in laboratory animals [30].

**2.10. Trifluridine (3FT) and vidarabine (Vira-A)**

testing are controversial [32–34].

**3. Nonnucleoside compounds**

**3.1. Abitylguanide**

This piperazinone is a result of a large screening of low-molecular substances, embracing chemical libraries of in total more than 25,000 compounds. A prospective selection of the compounds was based on protein-protein and protein-DNA interaction [40, 41]. The derivative 15D8 showed substantial anti-AdV activity (AdV 5 and AdV16 models) in dose-dependent manner at high MOI (15,000 vp/cell) with little or absent cytotoxicity at low micromolar concentration. The compound selectively inhibits AdV DNA replication in the nucleus. It is possible 15D8 to interact with viral proteins essential for DNA, including precursor of the terminal protein (pTP), AdV DNA polymerase or the DNA-binding protein (DBP). 15D8 could be considered as a potential candidate for the development of a new class of antiviral compounds to treat AdV infections [42].
