Inhibition of human herpesvirus 6 replication by 9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine (2HM-HBG) and other antiviral compounds

Abstract

The in vitro susceptibilities of human herpesvirus 6 to foscarnet; the guanosine analogs acyclovir, ganciclovir, and two isomers of 9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine; and the thymidine analogs 3'-azido-3'-deoxythymidine and 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil were investigated. All compounds except 3'-azido-3'-deoxythymidine and 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil inhibited human herpesvirus 6 replication. The highest in vitro selectivity was obtained for 9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine.

Inhibition of SIV and HIV-2 Replication in Cynomolgus Monkeys by (-)9-[4-Hydroxy-2-(Hydroxymethyl)-Butyl]Guanine (H2G)

“…The (+)enantiomer of H2G at 3x10 mg kg-1 day-1 did not show any inhibition of SIV sm replication in monkeys (Fig. 2a) in agreement with the earlier observation that the (-)enantiomer was more inhibitory than the (+)enantiomer to HSV, VZV (Abele et al, 1991) and HHV-6 replication (Akesson- Johansson et al, 1990). The enantiomeric mixture (±)H2G at 3x25 mg kg-1 day-1 was inhibitory (Fig.…”

“…(-)9-[4-Hydroxy-2-(hydroxymethyl)butyl]guanine (H2G; earlier abbreviated 2HM-HBG) is an acyclic guanosine analogue which was earlier found to inhibit replication in vitro of herpes simplex virus 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV) and human herpesvirus type 6 (HHV-6), but not cytomegalovirus (CMV) (Larsson et al, 1986;Abele et al, 1987;1988b;Abele, 1988a;Lake-Bakaaret al, 1988;Akesson-Johansson et al, 1990). These effects were largely confined to the (-)enantiomer of H2G which is phosphorylated by herpesvirus thymidine kinases, and after further phosphorylation by cellular kinases to the triphosphate inhibits herpesvirus DNA polymerases.…”

Human herpesvirus-6 encephalitis after allogeneic hematopoietic cell transplantation: What we do and do not know

“…Delayed initiation of antiviral therapy will give the HHV-6 time to expand in the brain. Studies of in vitro efficacy [73][74][75][76] have identified PFA as showing the highest selectivity among anti-HHV-6 compounds, and PFA is therefore considered the preferred treatment option for HHV-6 encephalitis. Combination therapy with PFA and GCV 50,51 may be more effective than monotherapy, but the benefits and additional risks have yet to be assessed.…”

Real-Time PCR as a Versatile Tool for Investigating the Susceptibility of Human Herpesvirus 6 to Antiviral Agents

“…These findings point out the need for readily accessible susceptibility assays to detect HHV-6 resistance as well as phenotypic tests investigating the replication capacity (fitness) of resistant viruses to understand the dynamics of resistance emergence. Different methods, such as evaluation of cytopathic effect, immunofluorescence assay, DNA hybridization, and flow cytometry, have been used previously (2,3,8,11). However, these approaches remained limited by the low infectious titers of HHV-6 stocks and the long incubation times (at least 7 days of culture) necessary to measure relevant markers of virus replication.…”