In search of effective anti-HHV-6 agents

Abstract

Since HHV-6, like HCMV, is a beta-herpesvirus, anti-HCMV drugs such as (val)ganciclovir, foscarnet and cidofovir may, by extrapolation, be advocated for the treatment of HHV-6 infections. At present, no prime candidate for the treatment of HHV-6 infections has been identified or even proposed, which means that the search for antiviral drugs effective against HHV-6-associated diseases should be encouraged. In essence, this search is going into two directions: nucleoside and non-nucleoside analogues. To the first category belong S2242, an N7-substituted purine acyclic derivative; A-5021, a cyclopropyl nucleoside analogue; cyclopropavir, a methylene cyclopropane analogue; lipophilic ester prodrugs of the acyclic nucleoside phosphonate cidofovir; and various other "old" and "new" acyclic nucleoside phosphonate analogues including those derived from the 2, 4-diaminopyrimidine (DAPy) skeleton. To the non-nucleoside category belong a number of quinoline-3-carboxamide, aryl sulfone, benzimidazole riboside and phenylenediamine sulfonamide derivatives which could be further optimized from a structure-activity relationship (SAR) viewpoint so as to specifically target HHV-6 replication. Also, specific protein kinase inhibitors may be pursued as anti-HHV-6 agents, a representative example being the compound CMV423 which, being inhibitory to (cellular) protein tyrosine kinases, exhibits potent and selective activity against HHV-6.