Inhibition of Epstein-Barr Virus Replication by a Benzimidazole l -Riboside: Novel Antiviral Mechanism of 5,6-Dichloro-2-(Isopropylamino)-1-β- l -Ribofuranosyl-1H-Benzimidazole

Abstract

Although a number of antiviral drugs inhibit replication of Epstein-Barr virus (EBV) in cell culture, and acyclovir (ACV) suppresses replication in vivo, currently available drugs have not proven effective for treatment of EBV-associated diseases other than oral hairy leukoplakia. Benzimidazole riboside compounds represent a new class of antiviral compounds that are potent inhibitors of human cytomegalovirus (HCMV) replication but not of other herpesviruses. Here we characterize the effects of two compounds in this class against lytic replication of EBV induced in a Burkitt lymphoma cell line latently infected with EBV. We analyzed linear forms of EBV genomes, indicative of lytic replication, and episomal forms present in latently infected cells by terminal probe analysis followed by Southern blot hybridization as well as the high-molecular-weight unprocessed viral DNA by pulsed-field gel electrophoresis. d-Ribofuranosyl benzimidazole compounds that act as inhibitors of HCMV DNA maturation, including BDCRB (5,6-dichloro-2-bromo-1-β-d-ribofuranosyl-1H-benzimidazole), did not affect the accumulation of high-molecular-weight or monomeric forms of EBV DNA in the induced cells. In contrast, the generation of linear EBV DNA as well as precursor viral DNA was sensitive to thel-riboside 1263W94 [5,6-dichloro-2-(isopropylamino)-1-β-l-ribofuranosyl-1H-benzimidazole]. The 50% inhibitory concentration range for 1263W94 was 0.15 to 1.1 μM, compared with 10 μM for ACV. Thus, 1263W94 is a potent inhibitor of EBV. In addition, 1263W94 inhibited the phosphorylation and the accumulation of the essential EBV replicative cofactor, early antigen D.

Conserved herpesvirus protein kinases

“…5,6-dichloro-2-(isopropylamino)-1,ß-L-ribofuranosyl-1-H-benzimidazole (1263W94 or maribavir, MBV) [95,96] (Fig. 1) is a potent and selective inhibitor of HCMV and EBV replication [97][98][99], but is inactive against HSV-1 and -2, VZV, HHV-6 and -7, and KSHV [98]. MBV showed significant antiviral potency in vitro against different HCMV strains, including strains resistant to GCV (mutations at 460, 520, 594 in pUL97), foscarnet (Thr700Ala in the viral polymerase) and BDCRB (Asp344Glu and Ala355Val in pUL89) [97,100,101].…”

Antiviral Drugs for EBV

“…Maribavir (MBV) is an investigational oral benzimidazole L-riboside with significant activity against both HCMV and EBV but not other herpesviruses [ 19 , 20 ]. Maribavir has more specific antiviral properties and fewer adverse side effects compared with currently approved anti-HCMV drugs.…”

“…In contrast to HCMV, the activity of MBV against EBV could not be ascribed to direct inhibition of the EBV PK (BGLF4). In fact, MBV treatment was shown to inhibit the phosphorylation of the EBV DNA processivity factor (BMRF1) [ 20 ]. Unlike ACV that has little effect on EBV RNAs, MBV inhibits the expression of multiple RNAs.…”

Novel Therapies for Cytomegalovirus Disease

“…Maribavir shows excellent activity against both laboratory and clinical strains of CMV, including those that are resistant to ganciclovir [177]. In a murine model, maribavir was effective in inhibiting CMV replication by approximately 30-to 3,000-fold in comparison to the negative control [178].…”