摘要
Herpesvirus capsid assembly proceeds via a non DNA containing capsid with an internal scaffold core that is not present in mature virions. The scaffold is composed of the viral protease and assembly protein (AP) and proteolytic processing of these proteins is essential for capsid maturation in order to produce infectious virions. In human cytomegalovirus (HCMV), the protease is expressed as a precursor protein that undergoes autocatalytic cleavage to free the catalytic domain of the enzyme located in the N-terminal 256 amino acids. Our medicinal chemistry efforts towards the development of inhibitors of HCMV protease have generated a series of monocyclic β-lactam inhibitors of the catalytic domain. We have evaluated the activity of these inhibitors on the processing of the protease precursor as well as the processing of the assembly protein using cells transfected with the protease and AP, and in cells infected with HCMV. These protease inhibitors exhibited concentration dependant inhibition of the protease precursor processing as well as inhibition of the AP processing by the protease catalytic domain in transfected cells. When evaluated in infected cells, accumulation of the protease precursor and the assembly protein precursor could be observed in cells treated with these inhibitors. The results of this study suggest that these β-lactam inhibitors can inhibit both forms of HCMV protease in transfected and in infected cells. Experiments are in progress to correlate the inhibition of protease and assembly protein processing with effects on DNA encapsidation and maturation of capsids to form infectious virions following treatment with these inhibitors.