**6. Inhibition of Major IE Gene Expression by Small Molecule Chemical Inhibitors**

#### *6.1. Introduction*

Inhibition of major IE gene expression can be achieved by identification of small molecules that directly or indirectly inhibit activation of the MIEP and thus prevent IE gene transcription and translation (Figure 2). The complexity of MIEP regulation and its dependence on host cell signalling pathways and transcription machinery (see Section 2.1) means that numerous host factors are potential drug targets. Activation of key host cell signalling pathways is dependent on post-translational phosphorylation events mediated by kinases, and thus kinase inhibitors have been largely implicated in IE gene expression inhibition. Host "epigenetic" factors are also potential targets to lock down IE transcription and hence inhibit viral replication and reactivation from latency. In addition, viral proteins are known to be directly involved in IE gene expression or regulation of host cell signalling pathways exploited by HCMV to activate IE gene expression. However, compounds targeting these viral proteins are considered beyond the scope of this review, as they would contribute to their own specific drug classes.

Small molecules that inhibit IE gene expression have been identified using a variety of strategic approaches; (i) exploitation of existing compounds that inhibit cell signalling pathways modulated by HCMV infection to facilitate MIEP activation and IE gene expression, (ii) targeted-screening of compound libraries composed of molecules that inhibit key cellular signalling components, e.g., kinase inhibitors, (iii) cell-based assays designed to discover novel molecules that target the early steps of HCMV replication and (iv) testing of compounds that have anecdotal evidence suggesting that they may have antiviral activity. Groups of related compounds have been identified using a combination of these approaches. Key groups of molecules are discussed below, although it should be noted that, in general, the small molecules that have thus far been identified have not had their mechanism of action fully elucidated.
