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Chemical Compound Review

AC1L3VEW     (2S)-2-[5,6-dichloro-2- (propan-2...

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Disease relevance of Maribavir


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


Biological context of Maribavir


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].


  1. Mutations in the human cytomegalovirus UL27 gene that confer resistance to maribavir. Chou, S., Marousek, G.I., Senters, A.E., Davis, M.G., Biron, K.K. J. Virol. (2004) [Pubmed]
  2. Inhibition of Epstein-Barr virus replication by a benzimidazole L-riboside: novel antiviral mechanism of 5, 6-dichloro-2-(isopropylamino)-1-beta-L-ribofuranosyl-1H-benzimidazole. Zacny, V.L., Gershburg, E., Davis, M.G., Biron, K.K., Pagano, J.S. J. Virol. (1999) [Pubmed]
  3. The human cytomegalovirus UL97 protein kinase, an antiviral drug target, is required at the stage of nuclear egress. Krosky, P.M., Baek, M.C., Coen, D.M. J. Virol. (2003) [Pubmed]
  4. Phase I dose escalation trial evaluating the pharmacokinetics, anti-human cytomegalovirus (HCMV) activity, and safety of 1263W94 in human immunodeficiency virus-infected men with asymptomatic HCMV shedding. Lalezari, J.P., Aberg, J.A., Wang, L.H., Wire, M.B., Miner, R., Snowden, W., Talarico, C.L., Shaw, S., Jacobson, M.A., Drew, W.L. Antimicrob. Agents Chemother. (2002) [Pubmed]
  5. Preclinical and toxicology studies of 1263W94, a potent and selective inhibitor of human cytomegalovirus replication. Koszalka, G.W., Johnson, N.W., Good, S.S., Boyd, L., Chamberlain, S.C., Townsend, L.B., Drach, J.C., Biron, K.K. Antimicrob. Agents Chemother. (2002) [Pubmed]
  6. Specific phosphorylation of exogenous protein and peptide substrates by the human cytomegalovirus UL97 protein kinase. Importance of the P+5 position. Baek, M.C., Krosky, P.M., He, Z., Coen, D.M. J. Biol. Chem. (2002) [Pubmed]
  7. Human cytomegalovirus UL97 Kinase is required for the normal intranuclear distribution of pp65 and virion morphogenesis. Prichard, M.N., Britt, W.J., Daily, S.L., Hartline, C.B., Kern, E.R. J. Virol. (2005) [Pubmed]
  8. Resistance of human cytomegalovirus to the benzimidazole L-ribonucleoside maribavir maps to UL27. Komazin, G., Ptak, R.G., Emmer, B.T., Townsend, L.B., Drach, J.C. J. Virol. (2003) [Pubmed]
  9. Maribavir antagonizes the antiviral action of ganciclovir on human cytomegalovirus. Chou, S., Marousek, G.I. Antimicrob. Agents Chemother. (2006) [Pubmed]
  10. Maribavir sensitivity of cytomegalovirus isolates resistant to ganciclovir, cidofovir or foscarnet. Drew, W.L., Miner, R.C., Marousek, G.I., Chou, S. J. Clin. Virol. (2006) [Pubmed]
  11. Maribavir Pharmacokinetics and the Effects of Multiple-Dose Maribavir on Cytochrome P450 (CYP) 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A, N-Acetyltransferase-2, and Xanthine Oxidase Activities in Healthy Adults. Ma, J.D., Nafziger, A.N., Villano, S.A., Gaedigk, A., Bertino, J.S. Antimicrob. Agents Chemother. (2006) [Pubmed]
  12. Effect of cell culture conditions on the anticytomegalovirus activity of maribavir. Chou, S., Van Wechel, L.C., Marousek, G.I. Antimicrob. Agents Chemother. (2006) [Pubmed]
  13. Maribavir (ViroPharma). Lu, H., Thomas, S. Current opinion in investigational drugs (London, England : 2000) (2004) [Pubmed]
  14. N-methylpurine DNA glycosylase and 8-oxoguanine dna glycosylase metabolize the antiviral nucleoside 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole. Lorenzi, P.L., Landowski, C.P., Brancale, A., Song, X., Townsend, L.B., Drach, J.C., Amidon, G.L. Drug Metab. Dispos. (2006) [Pubmed]
  15. Interactions among antiviral drugs acting late in the replication cycle of human cytomegalovirus. Evers, D.L., Komazin, G., Shin, D., Hwang, D.D., Townsend, L.B., Drach, J.C. Antiviral Res. (2002) [Pubmed]
  16. Pivotal role of animal models in the development of new therapies for cytomegalovirus infections. Kern, E.R. Antiviral Res. (2006) [Pubmed]
  17. Effects of maribavir and selected indolocarbazoles on Epstein-Barr virus protein kinase BGLF4 and on viral lytic replication. Gershburg, E., Hong, K., Pagano, J.S. Antimicrob. Agents Chemother. (2004) [Pubmed]
  18. Phosphorylation of the Epstein-Barr virus (EBV) DNA polymerase processivity factor EA-D by the EBV-encoded protein kinase and effects of the L-riboside benzimidazole 1263W94. Gershburg, E., Pagano, J.S. J. Virol. (2002) [Pubmed]
  19. The human cytomegalovirus UL44 protein is a substrate for the UL97 protein kinase. Krosky, P.M., Baek, M.C., Jahng, W.J., Barrera, I., Harvey, R.J., Biron, K.K., Coen, D.M., Sethna, P.B. J. Virol. (2003) [Pubmed]
  20. Phase I safety and pharmacokinetic trials of 1263W94, a novel oral anti-human cytomegalovirus agent, in healthy and human immunodeficiency virus-infected subjects. Wang, L.H., Peck, R.W., Yin, Y., Allanson, J., Wiggs, R., Wire, M.B. Antimicrob. Agents Chemother. (2003) [Pubmed]
  21. Development of novel benzimidazole riboside compounds for treatment of cytomegalovirus disease. Chulay, J., Biron, K., Wang, L., Underwood, M., Chamberlain, S., Frick, L., Good, S., Davis, M., Harvey, R., Townsend, L., Drach, J., Koszalka, G. Adv. Exp. Med. Biol. (1999) [Pubmed]
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