**1. Role of adenoviruses in human pathology**

Adenoviruses (AdVs) [1] occupy a significant place in the human pathology [2]. It was established that 30–70% of the human population in Europe and North America shows a seroprevalence to AdVs (cit. in [3]). These viruses are causative agents of wide range of human diseases, showing varying tissue tropism. They are generally middle and self-limiting. Among them, large place is occupied by acute respiratory tract diseases, especially in children [4]. Conjunctivitis is very often registered in these infections. More severe course manifests viral

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

gastroenteritis, especially in infants, as well as hemorrhagic cystitis, and in rare cases, hepatitis, myocarditis, meningoencephalitis or nephritis [5, 6]. AdVs are characteristic with their severe course in persons with hereditary decreased or impaired immune system: (1) hereditary immunodeficiency; (2) in persons transplant recipients treated with immunosuppressive agents; (3) AIDS. In such patients, the abovementioned clinical manifestations are particularly prone to disseminated disease frequently show a fatal outcome, in children mortality rate attains 83% [7–9]. EKC is another serious and very frequent AdV induced disease, extremely often with social importance [10–14].

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

inhibition of late genes

5-MP dehydrogenese (decreased GTP pools) • Viral polymerases inhibition (RNA capping activity of viral transcripts) • Lethal mutagenesis of viral RNA genomes ("error catastrophe")

proteins

expression

Ganciclovir AdV DNA synthesis,

Alovudine AdV DNA polymerase

Vidarabine DNA synthesis

Ribavirin • Inhibition of inosin-

Abitylguanide-HCl Ligand of AdV capsid

Trifluridine DNA synthesis *Local application*

Zalcitabine

**clinical trial**

treated each)

*Local application* ZIRGAN

Chemotherapy of Adenovirus Infections http://dx.doi.org/10.5772/intechopen.79160 15

Three double-blind trials: two in US and one in Germany (40 placebo and 40 ZIRGAN

GCV in combination with the microbicide povidon-iodine

*General application in immunocompromized patients*

*Local application in EKC patients* ADENOSTATIN COLLYRIUM Two placebo-controlled randomised trials on 349 EKC patients (151 and 198, respectively) carried out in 1973/74; three placebocontrolled trials in latest 80th

years

The major problem of AdVs infections is the absence of chemotherapeutic agents not only for the clinical practice, but even the absence at strong anti-adenovirals in experimental research. This is pointed in all manuals of virology considering AdVs and AdV-induced infections, in the review articles and even in all encyclopedic sources. Evidently, development of an effective antiviral treatment is a principal task.

This chapter presents a concentrated view on the investigations of experimental chemotherapy of AdV infections and results of their clinical application (**Table 1**).


gastroenteritis, especially in infants, as well as hemorrhagic cystitis, and in rare cases, hepatitis, myocarditis, meningoencephalitis or nephritis [5, 6]. AdVs are characteristic with their severe course in persons with hereditary decreased or impaired immune system: (1) hereditary immunodeficiency; (2) in persons transplant recipients treated with immunosuppressive agents; (3) AIDS. In such patients, the abovementioned clinical manifestations are particularly prone to disseminated disease frequently show a fatal outcome, in children mortality rate attains 83% [7–9]. EKC is another serious and very frequent AdV induced disease, extremely

The major problem of AdVs infections is the absence of chemotherapeutic agents not only for the clinical practice, but even the absence at strong anti-adenovirals in experimental research. This is pointed in all manuals of virology considering AdVs and AdV-induced infections, in the review articles and even in all encyclopedic sources. Evidently, development of an effec-

This chapter presents a concentrated view on the investigations of experimental chemother-

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

Cidofovir AdV DNA polymerase *Local application in EKC* 

Brincyclovir AdV DNA polymerase *Oral application*

elongation

(S)-HPMPA AdV DNA chain

(S)-HPMPO-DAPy AdV DNA polymerase

**clinical trial**

*Oral application in immunocompromised* 

Controlled clinical pilot study of combination with cyclosporine

*patients*

*patients* VISTID

CHIMERIX

Phase II clinical trial

apy of AdV infections and results of their clinical application (**Table 1**).

often with social importance [10–14].

14 Adenoviruses

tive antiviral treatment is a principal task.

[18–20]. Romanowski and Gordon [21] found efficacy of topical 0.5% cidofovir on several human adenoviruses (AdV1, AdV5 and AdV6) in the New Zealand rabbit ocular model. AdV type B and type C-induced pneumonia registered in mice and in cotton rats [22] could be used

Chemotherapy of Adenovirus Infections http://dx.doi.org/10.5772/intechopen.79160 17

This compound is a lipidic conjugate of cidofovir. It prevents AdV induced mortality in a

Its anti-AdV effect has the same mechanism as cidofovir—inhibition of the AdV DNA chain

This compound proved active against multiple AdV serotypes in vitro and was effective versus AdV-C6 in hamsters immunosuppressed by cyclophosphamide. Administered orally USC-187 prevented or significantly decreased mortality, virus titers and liver pathology up to 4 days post AdV i.v. challenge. Applied in a respiratory AdV-C6 challenge model USC-187

The compound anti-AdV activity registered was slightly inferior than that of cidofovir and

In vitro manifested a marked activity on AdV replication with selectivity index exceeding

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

**2.5. (S)-HPMPO-DAPy [2,4-diamino-6-[3-hydroxy-2-(phosphonomethoxy)-propoxy]**

for in vivo treatment with antivirals.

manifested symptoms of toxicity [25].

elongation [24].

**pyrimidine)**

HPMPA [26].

cidofovir [26].

**2.7. Ganciclovir (GCV)**

**2.2. Brincyclovir (BCV; hexadecyloxypropyl-cidofovir; CMX001)**

**2.4. USC-187 (alkyl tyrosinamide-ester prodrug of HPMPA)**

**2.6. (S)-2242 [2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine**

**2.3. (S)-HPMPA [(S)-9-(3-hydroxy-2-phosphonomethoxypropyl)adenine**

permissive, immunosuppressed animal model [23].

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