*6.3. NF-*κ*B Inhibitors*

HCMV infection modulates several cell signalling pathways, including the NF-κB and PI3K/AKT pathways, in order to facilitate MIEP activation and IE gene expression (see Section 2.1) [183]. Artemsinin and derivatives, which interfere with the NF-κB pathway, were discussed in Section 6.2. The mode of action of these compounds was identified after testing for anti-HCMV activity based on their anti-malarial properties. An alternative strategy for identification of anti-HCMV compounds that inhibit major IE gene expression, is to exploit existing compounds already known to inhibit cell signalling pathways modulated by HCMV. A rich source of compounds that could be repurposed as anti-HCMV compounds are the numerous NF-κB pathway inhibitors that have been identified for reasons unrelated to HCMV [346,347]. For example, IKK2 inhibitor AS602868 targets a crucial step in NF-κB pathway activation: the phosphorylation and subsequent degradation of IκB by the IKK complex [348,349]. Testing of AS602868 showed that this compound prevents HCMV mediated NF-κB pathway activation, resulting in significant inhibition of IE gene expression, HCMV replication and HCMV-induced host cell inflammatory response without cytotoxicity [350]. HCMV infection also up-regulates the PI3K/AKT pathway leading to activation of NF-κB in a PI3K-dependent manner. LY294002, a PI3K inhibitor, significantly reduces HCMV IE1/2 expression, viral DNA replication and viral titers [156,351]. Disruption of the PI3K pathway and subsequent AKT and NF-κB activation has been suggested as a possible mechanism of action for heat shock protein 90 (hsp90) inhibitors geldanamycin and 17AAG, which significantly inhibit HCMV replication by affecting IE protein production and hence subsequent steps in HCMV productive replication [351,352]. The examples discussed above demonstrate the value of repurposing existing cell signalling pathway inhibitors for targeting HCMV by inhibition of major IE gene expression.
