, 2011). Thus, in view of the growing numbers of immunosuppressed patients, the development of alternative anti-adenovirus treatment options is required Ipatasertib chemical structure to decrease adenovirus-mediated mortality among immunocompromised patients, and also to decrease economic losses caused by milder forms of adenovirus-related disease. RNA interference (RNAi) is a post-transcriptional mechanism of gene silencing conserved among

eukaryotic cells (Carthew and Sontheimer, 2009, Ghildiyal and Zamore, 2009, Huntzinger and Izaurralde, 2011, Hutvagner and Simard, 2008 and Kawamata and Tomari, 2010). It is mediated through small double-stranded RNAs (dsRNAs), of ∼21–25 nt in length, which guide the RNA-induced silencing complex (RISC) to the respective target mRNAs (Fire et al., 1998). Depending on the degree of complementarity between the so-called antisense (or guide) strand of the dsRNA and target mRNA, RNAi can bring about the cleavage of the mRNA (in the case of full or nearly full complementarity), accelerated degradation (as a consequence of deadenylation), or translational repression. Following the discovery

that the introduction of synthetic small interfering RNAs (siRNAs) into cells can trigger RNAi (Elbashir et al., 2001), this mechanism was rapidly harnessed as a tool to silence disease-associated human, and also viral genes (Davidson and McCray, 2011). Since then, siRNA-mediated silencing of viral genes has been employed Selleckchem MEK inhibitor to inhibit the replication of a variety of DNA and RNA viruses, in vitro and also in vivo ( Arbuthnot, 2010, Haasnoot et al., 2007 and Zhou and Rossi, 2011).

Adenoviruses contain a linear dsDNA genome, ∼36 kb long. The first gene to be expressed during the infection cycle is E1A. This gene has a central role, because it reprograms the cell in a way that promotes efficient virus replication (Berk, 2005, Pelka et al., 2008 and Zhao et al., 2003). Deletion of E1A renders adenoviruses replication deficient. E1A expression ultimately leads to the activation of other early and late promoters and triggers the onset of viral DNA replication. Viral DNA replication is dependent on three viral proteins: the viral DNA polymerase; the preterminal protein (pTP); and the DNA-binding protein (DBP) (de Jong et al., 2003). Besides creating PD184352 (CI-1040) dsDNAs for packaging into capsids (accomplished with the help of the IVa2 protein) (Zhang and Imperiale, 2003), replication of the adenoviral genome activates the expression of other viral genes, e.g., IVa2 ( Flint, 1986 and Iftode and Flint, 2004) and genes transcribed from the major late promoter (MLP) ( Shaw and Ziff, 1980). Upregulation of major late (ML) gene expression also involves the IVa2 protein ( Tribouley et al., 1994), and results in the synthesis of gene products that primarily constitute structural components of the virion or are involved in its assembly. The major component of the capsid is the hexon protein ( Russell, 2009).