Disease relevance of Maribavir

• Mutations in the human cytomegalovirus UL27 gene that confer resistance to maribavir [1].
• Thus, 1263W94 is a potent inhibitor of EBV [2].
• However, capsids were rare in the cytoplasm of mutant-infected or maribavir-treated cells; the magnitudes of these decreases in cytoplasmic capsids were similar to those for virus yield [3].
• A phase I study was conducted to determine the pharmacokinetics (PK), anti-HCMV activity, and safety of 1263W94 administered as multiple oral doses to human immunodeficiency virus type 1-infected adult male subjects with asymptomatic HCMV shedding [4].
• In the mouse lymphoma assay, 1263W94 was mutagenic in the absence of the rat liver S-9 metabolic activation system, with equivocal results in the presence of the S-9 mix [5].

High impact information on Maribavir

• Phosphorylation of the Ser-38 peptide by UL97 occurred on Ser-38 and was specifically sensitive to maribavir, whereas phosphorylation of this peptide by cAMP-dependent protein kinase occurred on Ser-36 [6].
• These structures were also observed in infected cells treated with the UL97 kinase inhibitor maribavir [7].
• Previous drug selection experiments resulted in the isolation of a human cytomegalovirus (CMV) UL97 phosphotransferase mutant resistant to the benzimidazole compound maribavir (1263W94), reflecting the anti-UL97 effect of this drug [1].
• Marker transfer experiments confirmed that UL27 mutations conferred maribavir resistance [1].
• However, no mutations were found in UL97 or other relevant open reading frames that could explain resistance to maribavir [8].

Chemical compound and disease context of Maribavir

• Maribavir antagonizes the antiviral action of ganciclovir on human cytomegalovirus [9].
• Maribavir sensitivity of cytomegalovirus isolates resistant to ganciclovir, cidofovir or foscarnet [10].

Biological context of Maribavir

• The 50% inhibitory concentration range for 1263W94 was 0.15 to 1 [2].
• Compared with wild-type virus, there was little or no decrease in immediate-early gene expression, viral DNA synthesis, late gene expression, or packaging of viral DNA into nuclease-resistant structures in mutant-infected or maribavir-treated cells under conditions where the virus yield was severely impaired [3].
• Understanding UL97 function and maribavir action should help elucidate this interesting biological process and help identify new antiviral drug targets for an important pathogen in immunocompromised patients [3].
• The pharmacokinetics of maribavir following a single dose and after 10 days of treatment were similar, with minimal accumulation at steady state [11].
• Mean oral bioavailability of 1263W94 was >90% in rats and approximately 50% in monkeys [5].

Anatomical context of Maribavir

• In monkeys, 1263W94 levels in the brain, cerebrospinal fluid, and vitreous humor ranged from 4 to 20%, 1 to 2%, and <1%, of corresponding concentrations in plasma, respectively [5].
• 1263W94 was primarily distributed in the gastrointestinal tract of rats but did not cross the blood-brain barrier [5].
• 1263W94 demonstrated in vivo anti-HCMV activity in semen at all of the dosage regimens tested, with mean reductions in semen HCMV titers of 2.9 to 3.7 log(10) PFU/ml among the four regimens evaluated for anti-HCMV activity [4].
• The cytomegalovirus UL97 kinase inhibitor maribavir suppressed viral growth more effectively in lung fibroblasts than in skin fibroblasts, and some cellular kinase inhibitors enhanced its antiviral activity [12].
• ViroPharma, under license from GlaxoSmithKline, is developing maribavir, a DNA synthesis inhibitor for the potential prevention and treatment of human cytomegalovirus infections related to transplants (including solid organ and hematopoietic stem cells), congenital transmission, and in patients with HIV infection [13].

Associations of Maribavir with other chemical compounds

• These studies showed that OGG1 was not able to bind a negative control, guanosine, yet BDCRB and maribavir were stabilized through interactions with various binding site residues, including Phe319, His270, Ser320, and Asn149 [14].
• Examination of drug-drug interactions in cell culture assays measuring inhibition of HCMV replication revealed strong synergism for the combination of BDCRB with 1263W94, and for combinations of 1263W94 with cidofovir (CDV) and foscarnet (PFA), but not with GCV [15].
• The SCID-hu mouse models in which human tissue is infected with human CMV has been very useful in the development of new antiviral agents such as maribavir and cyclopropavir [16].

Gene context of Maribavir

• Here we show that only one of these indolocarbazoles (K252a), but not maribavir, inhibits autophosphorylation of the EBV PK, BGLF4 [17].
• Metabolism of 1263W94 to its primary metabolite, an N-dealkylated analog, appeared to be mediated via the isozyme CYP3A4 in humans [5].
• In the present report the effect of 1263W94 on the phosphorylation pattern of the EBV DNA polymerase processivity factor, EA-D, during viral reactivation in latently EBV-infected Akata cells is analyzed [18].
• Testing the recombinants for sensitivity to maribavir narrowed the locus of resistance to genes UL26 to UL32 [8].
• Two-dimensional gel electrophoresis revealed the absence of specific phosphorylated forms of UL44 in immunoprecipitates from lysates of cells infected with a UL97 null mutant virus or with wild-type virus in the presence of maribavir [19].

Analytical, diagnostic and therapeutic context of Maribavir

• Viable UL27 deletion mutants were created by recombination and showed slight growth attenuation and maribavir resistance in cell culture [1].
• 1263W94 was rapidly absorbed following oral administration, with peak concentrations in plasma (C(max)) occurring 1 to 3 h after dosing [20].
• Ongoing and planned clinical trials that will study the safety and tolerability of repeated dosing and evaluate the in vivo antiviral activity and ocular penetration of 1263W94, will help to determine the potential of this drug as an improved therapy for CMV disease [21].

References