**2.7. Ganciclovir (GCV)**

**2. Nucleoside/nucleotide analogues**

**Table 1.** Compounds manifesting activity against human adenoviruses.

**VISTID]**

Digoxin and Digitoxin

16 Adenoviruses

2,4,5,7-Tetranitro-9 fluorenone

4-{4-[Benzyl(methyl)

amino]-2 hydroxybenzoyl} benzoic acid

resistant AdV mutants [16].

**2.1. Cidofovir [(S)-HPMPC; (S)-1-(3-hydroxy-2-phosphonomethoxypropyl)cytosine;** 

**Compound name Chemical structure Target Way of administration and** 

terminal protein pTP, AdV DNA polymerase and DNA-binding protein

Alter RNA splicing EIA activity gene early in AdV infection (late proteins E4 and F6 and the major late capsid hexon protein are

compromised)

Inhibits AdV cysteine protease (indispensable for the production of infectious AdV virions)

15D8 Ligand of precursors of

**clinical trial**

*General application(?)*

The antiviral effect of cidofovir is based on its transformation in the infected cells in di- and triphosphate and such way becoming an alternative substrate of the AdV DNA polymerase possessing higher affinity compared to cellular DNA polymerases (I, II and III) [15]. Sequence changes in a conserved region of the AdV DNA polymerase were established at cidofovir-

Cidofovir IC50 values in cell culture testing versus broad spectrum of AdVs are within 0.8– 17 μg/ml [17]. In in vivo testing in ocular infection with AdV (type C) of New Zealand rabbits and cotton rats the compound treatment is efficacious when administered as 0.5–1% eye drops This compound is known as a drug approved for the treatment of herpes infection (cytomegalovirus infection especially) was reported to be effective against human AdVs in vitro [27]. In cell culture GCV inhibits AdV5 replication and expression of late genes [28]. These authors established a marked effect of 3% GCV in cotton rat eyes, on replication and pathology of this virus [28] Ying et al. [29] tested the GCV administered locally for prophylactic or therapeutic effect in immunosuppressed (by cyclophosphamide) Syrian hamsters intravenously infected with human AdV5 and was established that the compound suppresses AdV5 replication in the liver and AdC5-induced pathology of infected hamsters thus mitigated the consequences of the AdV infection. It was showed that GCV inhibits AdV5 DNA synthesis and late gene expression. The slight increase in GCV phosphorylation in AdV infected cells established by 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 a possible mechanism of GCV suppressive effect on AdV DNA synthesis.

effect varied from 1.5 to 3.8 logs. A marked correlation was established between the value of inhibitory effect and belonging of tested AdVs to various subgroups, the strongest activity being found toward viruses of subgroup C (Rosen's subgroup III). The compound susceptible period of AdV 5 replication included the total growth cycle, but is especially pronounced during the exponential phase. This was established through timing-of-addition study in primary cell cultures of human embryo kidney cells. Electron microscopy study of AdV5 morphogenesis contributed substantially to the clearing-up of the mechanism of anti-AdV action of abitylguanide. It was registered that: (1) the compound decreased about 10-fold the percentage of cells in which mature or empty virions with the characteristic nuclear localization were observed; (2) a complete absence of paracrystals; (3) the number of cells with virus particles

Chemotherapy of Adenovirus Infections http://dx.doi.org/10.5772/intechopen.79160 19

The absence of crystalline inclusions established electron microscopically in our study correlated with the established pronounced decrease of infectivity and/or lower yields of viral progeny which is in line with the meaning [39] that the protein crystals might be involved in at late steps of the virus life cycle ensuring correct capsid assembly, virus maturation and infectivity. Discussing the mode of action of abitylguanide on AdV 5 replication it has to stress on the full coincidence of the data obtained electron microscopically with the results of the timing-of-addition study demonstrating the highly-pronounced compound-sensitivity of the virus growth in the exponential phase. On the basis of the mentioned data, abitylguanide can

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

Very surprising recently (2017), the cardiotonic steroids entered in the scope of the struggle with AdV infections. As a theoretic prerequisite of their effects were the data on dependents of AdV on the host pre-RNA splicing machinery for expression of its complete genome. On such base modulators of RNA splicing as digoxin and digitoxin could be considered as antivirals versus human AdVs. Grosso et al. [3] proved that both drugs reduced of a series of AdVs of four different species (A to D) by 2–3 logs. This is a result of affecting several steps needed for AdV genome replication (late proteins E4 or f6 and the major late capsid hexon protein is compromised). The authors proved that these two drugs altered EiA RNA splicing early in infection and partially blocked the translation from 12S and 13S to 9S RNA at later stages of

arranged in crystals in the nucleoplasm was strongly decreased [38].

be considered a ligand of AdV capsid protein(s) [38].

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

compounds to treat AdV infections [42].

**3.3. Cardiotonic steroids—digoxin and digitoxin**
