Small Molecule Inhibitors of Herpes Simplex Virus Type 1 Immediate Early Gene Expression

The only therapeutic agents that are currently available for the treatment of herpes simplex virus type 1 (HSV-1) infections are a small number of nucleoside analogues, each of which acts by inhibiting the replication of the DNA genome of this pathogen. The observations that these drugs fail to modulate the frequency of latent virus reactivation and that their effectiveness can be significantly weakened through the acquisition of viral resistance mutations argue that efforts to identify additional classes of HSV-1 inhibitors should continue. One stage in the viral life cycle that would seem to be an excellent target for the development of novel therapeutic agents is the expression of HSV-1 immediate early genes, as this represents a key regulatory checkpoint utilized not only during lytic infections but also reactivation from latent infections. Full activation of HSV-1 immediate early gene promoters requires two viral-encoded polypeptides, VP16 and ICP0, each of which stimulates transcription by effecting multiple interactions with host cell proteins. Although to date no small molecule inhibitors of the VP16 and ICP0 proteins themselves have been discovered, a number of compounds that interfere with host cell functions critical for immediate early gene expression have been described. Several of the latter molecules target previously identified proteins that are known to be critical for cell viability, such as the proteasome, cyclin-dependent kinases and nuclear transcription factors. Unfortunately, these compounds typically reveal narrow therapeutic margins and poor selectivity when their antiviral and cytotoxic properties are compared. However, a number of other small molecule inhibitors have recently been described that exhibit remarkable levels of selective inhibition of HSV-1 immediate early gene expression. Although the development of each of these compound series has been discontinued because of pharmacokinetic or toxicological concerns, further studies with these promising leads could lead to the identification of one or more novel cellular targets against which a new generation of antiherpesviral drugs may be discovered. (c) 2002 Prous Science. All rights reserved.