Benzimidazole analogs inhibit human herpesvirus 6

Abstract

Several benzimidazole nucleoside analogs, including 1H-β-D-ribofuranosyl-2-bromo-5,6-dichlorobenzimidazole (BDCRB) and 1H-β-L-ribofuranosyl-2-isopropylamino-5,6-dichlorobenzimidazole (maribavir [MBV]), inhibit the replication of human cytomegalovirus. Neither analog inhibited the related betaherpesvirus human herpesvirus 6 (HHV-6). Additional analogs of these compounds were evaluated against both variants of HHV-6, and two L-analogs of BDCRB had good antiviral activity against HHV-6A, as well as more modest inhibition of HHV-6B replication.

Fig. 1.

Structures of selected benzimidazole nucleoside analogs. Compound names and numerical designations are given in Table 1.

Fig. 2.

Inhibition of aggresome formation by the HHV-6B U69 kinase activity. Inhibition of the HHV-6B U69 kinase activity was evaluated in a transient aggresome formation assay in COS7 cells (A). The formation of aggresomes induced by the CMV pp65-GFP fusion protein is inhibited by the enzymatic activity of the U69 kinase coexpressed in the cells (compare cotransfected cells in row 1 to those expressing only pp65-GFP in row 4). The kinase null K219M mutant was unable to inhibit aggresome formation (row 2). MBV at a concentration of 15 μM also eliminated the ability of the HHV-6B U69 kinase to inhibit aggresome formation and indicated that the drug inhibited its enzymatic activity (row 3). Both genetic and pharmacologic evidence shows that kinase activity is required to inhibit aggresome formation. (B) The proportion of cells with aggresomes was quantified by counting at least 10 separate fields at the concentrations shown, with error bars representing the standard deviation values. MBV inhibited both the HHV-6B U69 kinase and the CMV UL97 kinase but exhibited greater efficacy against the UL97 kinase.