Inhibition of Ganciclovir-Susceptible and -Resistant Human Cytomegalovirus Clinical Isolates by the Benzimidazole l -Riboside 1263W94

Abstract

The average 50% inhibitory concentration (IC 50 ) values for AD169 were 0.22 ؎ 0.09 M 1263W94 and 5.36 ؎ 0.12 M ganciclovir. For 35 human cytomegalovirus (HCMV) clinical isolates the average IC 50 was 0.42 ؎ 0.09 M 1263W94, and for 26 ganciclovir-susceptible HCMV clinical isolates the average IC 50 was 3.78 ؎ 1.62 M ganciclovir. Nine HCMV clinical isolates that were resistant to ganciclovir were completely susceptible to 1263W94.Human cytomegalovirus (HCMV) causes considerable morbidity and mortality in the immunocompromised host (18,19). Organ transplant recipients suffer from retinitis, gastrointestinal disease, hepatitis, and pneumonia caused by HCMV infections, whereas AIDS patients suffer from HCMV-induced retinitis and other complications (1). The current Food and Drug Administration-approved chemotherapies for HCMV infections consist of ganciclovir, foscarnet, cidofovir, and fomivirsen (5,16,17,20). These antiviral drugs are effective against infections caused by HCMV; however, they are not ideal because of their toxicity and poor bioavailability. Furthermore, longterm treatment with these drugs often leads to the selection of drug-resistant mutants (6,8,9). Due to the problems associated with the currently used antiviral compounds for HCMV infection, there is an active search for more useful compounds to combat infections with HCMV.The benzimidazole ribonucleosides represent a new class of antiviral compounds that inhibit HCMV replication by blocking the processing of progeny viral DNA (4,10,22). In an attempt to make a more stable derivative of benzimidazole riboside 2-bromo-5,6-dichloro-1-␤-D-ribofuranosyl benzimidazole (BDCRB), the L form of the compound, was synthesized (4). The L-riboside benzimidazole analogue of BDCRB, 1263W94, has potent activity against HCMV laboratory strains and clinical isolates as well as Epstein-Barr virus (4, 23). Preliminary studies suggest that 1263W94 inhibits HCMV replication by blocking viral DNA synthesis, but not by an effect on the viral DNA polymerase or the phosphotransferase encoded by the UL97 gene (4).In this report, we show that 1263W94 inhibits the replication of the AD169 laboratory strain of HCMV and 35 HCMV clinical isolates at drug concentrations that are approximately 10-fold less than those required by ganciclovir. Nine of the 35 HCMV clinical isolates are resistant to ganciclovir, and several are also resistant to foscarnet and cidofovir (2,3,7,8,9,11).All of these drug-resistant HCMV clinical isolates are susceptible to 1263W94. These results show that 1263W94 inhibits the replication of both ganciclovir-susceptible and single-and multiple-drug-resistant HCMV clinical isolates, confirming reports that 1263W94 has a mode of action different from that of ganciclovir, foscarnet, and cidofovir (4). These results also suggest that this drug is potentially useful for treating patients infected with HCMV clinical isolates that are resistant to the currently used antiviral drugs.Determination of IC 50 values of 1263W94 and ganciclovir for HCMV laboratory str...

Preparation and ocular pharmacokinetics of ganciclovir liposomes

“…After application of GCV liposomes, the highest concentrations of GCV were found in the sclera and the cornea (1000-1500 ng/g), both of which are higher than the half maximal inhibitory concentration (IC 50 ) of GCV against CMV (900 ng/g). 16 The concentration s of GCV in the aqueous humor, lens, and vitreous humors in the liposome-treated group were found to be within the range of 100 to 500 ng/g, which were several times higher than those of the solution-treated group (30-300 ng/g). Because over 70% of À uid in vitreous humor moves toward the retina and exits the vitreous cavity through the retina, GCV concentration in vitreous humor could be used to evaluate the possible effectiveness of GCV against CMV retinitis.…”

The ULb′ Region of the Human Cytomegalovirus Genome Confers an Increased Requirement for the Viral Protein Kinase UL97

“…Although we are unaware of previous studies of UL97 mutants in HCMV strains that encode full-length ULb=s, at least two reports have examined the effects of MBV on clinical isolates (5,69). The use of infected cells as inocula may explain why the authors did not find an increased requirement for UL97 in their assays with clinical isolates.…”

Maribavir Inhibits Epstein-Barr Virus Transcription in Addition to Viral DNA Replication

“…It is much more potent than ACV, and more importantly, it is very active against HCMV strains that are resistant to either of these drugs (42,64). Therefore, MBV is an excellent candidate to prevent and treat HCMV diseases in high-risk patients based on its efficacy and safety profile in phase 1 clinical trials (32,63).…”