This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Biron, K. K.
Right arrow Articles by Koszalka, G. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Biron, K. K.
Right arrow Articles by Koszalka, G. W.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, August 2002, p. 2365-2372, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2365-2372.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Potent and Selective Inhibition of Human Cytomegalovirus Replication by 1263W94, a Benzimidazole L-Riboside with a Unique Mode of Action{dagger}

Karen K. Biron,1* Robert J. Harvey,1 Stanley C. Chamberlain,1 Steven S. Good,1 Albert A. Smith III,1 Michelle G. Davis,1 Christine L. Talarico,1 Wayne H. Miller,1 Robert Ferris,1 Ronna E. Dornsife,1 Sylvia C. Stanat,1 John C. Drach,2 Leroy B. Townsend,2 and George W. Koszalka1

GlaxoSmithKline, Research Triangle Park, North Carolina 27709,1 College of Pharmacy and School of Dentistry, University of Michigan, Ann Arbor, Michigan 481092

Received 31 August 2001/ Returned for modification 25 October 2001/ Accepted 15 January 2002

Benzimidazole nucleosides have been shown to be potent inhibitors of human cytomegalovirus (HCMV) replication in vitro. As part of the exploration of structure-activity relationships within this series, we synthesized the 2-isopropylamino derivative (3322W93) of 1H-ß-D-ribofuranoside-2-bromo-5,6-dichlorobenzimidazole (BDCRB) and the biologically unnatural L-sugars corresponding to both compounds. One of the L derivatives, 1H-ß-L-ribofuranoside-2-isopropylamino-5,6-dichlorobenzimidazole (1263W94), showed significant antiviral potency in vitro against both laboratory HCMV strains and clinical HCMV isolates, including those resistant to ganciclovir (GCV), foscarnet, and BDCRB. 1263W94 inhibited viral replication in a dose-dependent manner, with a mean 50% inhibitory concentration (IC50) of 0.12 ± 0.01 µM compared to a mean IC50 for GCV of 0.53 ± 0.04 µM, as measured by a multicycle DNA hybridization assay. In a single replication cycle, 1263W94 treatment reduced viral DNA synthesis, as well as overall virus yield. HCMV mutants resistant to 1263W94 were isolated, establishing that the target of 1263W94 was a viral gene product. The resistance mutation was mapped to the UL97 open reading frame. The pUL97 protein kinase was strongly inhibited by 1263W94, with 50% inhibition occurring at 3 nM. Although HCMV DNA synthesis was inhibited by 1263W94, the inhibition was not mediated by the inhibition of viral DNA polymerase. The parent benzimidazole D-riboside BDCRB inhibits viral DNA maturation and processing, whereas 1263W94 does not. The mechanism of the antiviral effect of L-riboside 1263W94 is thus distinct from those of GCV and of BDCRB. In summary, 1263W94 inhibits viral replication by a novel mechanism that is not yet completely understood.

* Corresponding author. Mailing address: Department of Clinical Virology, GlaxoSmithKline, 5 Moore Dr., Research Triangle Park, NC 27709. Phone: (919) 483-9310. Fax: (919) 315-5243. E-mail: kkb21173{at}gsk.com.

{dagger} This paper is dedicated to the memory of Mary Lou Hemphill.

Antimicrobial Agents and Chemotherapy, August 2002, p. 2365-2372, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2365-2372.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Zhu, J., Liao, G., Shan, L., Zhang, J., Chen, M.-R., Hayward, G. S., Hayward, S. D., Desai, P., Zhu, H. (2009). Protein Array Identification of Substrates of the Epstein-Barr Virus Protein Kinase BGLF4. J. Virol. 83: 5219-5231 [Abstract] [Full Text]  
  • Rechter, S., Scott, G. M., Eickhoff, J., Zielke, K., Auerochs, S., Muller, R., Stamminger, T., Rawlinson, W. D., Marschall, M. (2009). Cyclin-dependent Kinases Phosphorylate the Cytomegalovirus RNA Export Protein pUL69 and Modulate Its Nuclear Localization and Activity. J. Biol. Chem. 284: 8605-8613 [Abstract] [Full Text]  
  • Thomas, M., Rechter, S., Milbradt, J., Auerochs, S., Muller, R., Stamminger, T., Marschall, M. (2009). Cytomegaloviral protein kinase pUL97 interacts with the nuclear mRNA export factor pUL69 to modulate its intranuclear localization and activity. J. Gen. Virol. 90: 567-578 [Abstract] [Full Text]  
  • Chou, S. (2009). Diverse Cytomegalovirus UL27 Mutations Adapt to Loss of Viral UL97 Kinase Activity under Maribavir. Antimicrob. Agents Chemother. 53: 81-85 [Abstract] [Full Text]  
  • Schroer, J., Shenk, T. (2008). Inhibition of cyclooxygenase activity blocks cell-to-cell spread of human cytomegalovirus. Proc. Natl. Acad. Sci. USA 105: 19468-19473 [Abstract] [Full Text]  
  • Trofe, J., Pote, L., Wade, E., Blumberg, E., Bloom, R. D (2008). Maribavir: A Novel Antiviral Agent with Activity Against Cytomegalovirus. The Annals of Pharmacotherapy 42: 1447-1457 [Abstract] [Full Text]  
  • Kalejta, R. F. (2008). Tegument Proteins of Human Cytomegalovirus. Microbiol. Mol. Biol. Rev. 72: 249-265 [Abstract] [Full Text]  
  • Winston, D. J., Young, J.-A. H., Pullarkat, V., Papanicolaou, G. A., Vij, R., Vance, E., Alangaden, G. J., Chemaly, R. F., Petersen, F., Chao, N., Klein, J., Sprague, K., Villano, S. A., Boeckh, M. (2008). Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study. Blood 111: 5403-5410 [Abstract] [Full Text]  
  • Prichard, M. N., Sztul, E., Daily, S. L., Perry, A. L., Frederick, S. L., Gill, R. B., Hartline, C. B., Streblow, D. N., Varnum, S. M., Smith, R. D., Kern, E. R. (2008). Human Cytomegalovirus UL97 Kinase Activity Is Required for the Hyperphosphorylation of Retinoblastoma Protein and Inhibits the Formation of Nuclear Aggresomes. J. Virol. 82: 5054-5067 [Abstract] [Full Text]  
  • Hume, A. J., Finkel, J. S., Kamil, J. P., Coen, D. M., Culbertson, M. R., Kalejta, R. F. (2008). Phosphorylation of Retinoblastoma Protein by Viral Protein with Cyclin-Dependent Kinase Function. Science 320: 797-799 [Abstract] [Full Text]  
  • Goldwater, D. R., Dougherty, C., Schumacher, M., Villano, S. A. (2008). Effect of Ketoconazole on the Pharmacokinetics of Maribavir in Healthy Adults. Antimicrob. Agents Chemother. 52: 1794-1798 [Abstract] [Full Text]  
  • Chou, S., Marousek, G. I. (2008). Accelerated Evolution of Maribavir Resistance in a Cytomegalovirus Exonuclease Domain II Mutant. J. Virol. 82: 246-253 [Abstract] [Full Text]  
  • Hwang, J.-S., Kregler, O., Schilf, R., Bannert, N., Drach, J. C., Townsend, L. B., Bogner, E. (2007). Identification of Acetylated, Tetrahalogenated Benzimidazole D-Ribonucleosides with Enhanced Activity against Human Cytomegalovirus. J. Virol. 81: 11604-11611 [Abstract] [Full Text]  
  • Milbradt, J., Auerochs, S., Marschall, M. (2007). Cytomegaloviral proteins pUL50 and pUL53 are associated with the nuclear lamina and interact with cellular protein kinase C. J. Gen. Virol. 88: 2642-2650 [Abstract] [Full Text]  
  • Kamil, J. P., Coen, D. M. (2007). Human Cytomegalovirus Protein Kinase UL97 Forms a Complex with the Tegument Phosphoprotein pp65. J. Virol. 81: 10659-10668 [Abstract] [Full Text]  
  • Lee, S. A., Jung, M. (2007). The Nucleoside Analog Sangivamycin Induces Apoptotic Cell Death in Breast Carcinoma MCF7/Adriamycin-resistant Cells via Protein Kinase C{delta} and JNK Activation. J. Biol. Chem. 282: 15271-15283 [Abstract] [Full Text]  
  • Gershburg, E., Raffa, S., Torrisi, M. R., Pagano, J. S. (2007). Epstein-Barr Virus-Encoded Protein Kinase (BGLF4) Is Involved in Production of Infectious Virus. J. Virol. 81: 5407-5412 [Abstract] [Full Text]  
  • Schregel, V., Auerochs, S., Jochmann, R., Maurer, K., Stamminger, T., Marschall, M. (2007). Mapping of a self-interaction domain of the cytomegalovirus protein kinase pUL97. J. Gen. Virol. 88: 395-404 [Abstract] [Full Text]  
  • Izumiya, Y., Izumiya, C., Van Geelen, A., Wang, D.-H., Lam, K. S., Luciw, P. A., Kung, H.-J. (2007). Kaposi's Sarcoma-Associated Herpesvirus-Encoded Protein Kinase and Its Interaction with K-bZIP. J. Virol. 81: 1072-1082 [Abstract] [Full Text]  
  • Swan, S. K., Smith, W. B., Marbury, T. C., Schumacher, M., Dougherty, C., Mico, B. A., Villano, S. A. (2007). Pharmacokinetics of Maribavir, a Novel Oral Anticytomegalovirus Agent, in Subjects With Varying Degrees of Renal Impairment. J Clin Pharmacol 47: 209-217 [Abstract] [Full Text]  
  • Chou, S., Marousek, G. I. (2006). Maribavir antagonizes the antiviral action of ganciclovir on human cytomegalovirus.. Antimicrob. Agents Chemother. 50: 3470-3472 [Abstract] [Full Text]  
  • Chou, S., Van Wechel, L. C., Marousek, G. I. (2006). Effect of cell culture conditions on the anticytomegalovirus activity of maribavir.. Antimicrob. Agents Chemother. 50: 2557-2559 [Abstract] [Full Text]  
  • Lorenzi, P. L., Landowski, C. P., Brancale, A., Song, X., Townsend, L. B., Drach, J. C., Amidon, G. L. (2006). N-METHYLPURINE DNA GLYCOSYLASE AND 8-OXOGUANINE DNA GLYCOSYLASE METABOLIZE THE ANTIVIRAL NUCLEOSIDE 2-BROMO-5,6-DICHLORO-1-({beta}-D-RIBOFURANOSYL)BENZIMIDAZOLE. Drug Metab. Dispos. 34: 1070-1077 [Abstract] [Full Text]  
  • Prichard, M. N., Britt, W. J., Daily, S. L., Hartline, C. B., Kern, E. R. (2005). Human Cytomegalovirus UL97 Kinase Is Required for the Normal Intranuclear Distribution of pp65 and Virion Morphogenesis. J. Virol. 79: 15494-15502 [Abstract] [Full Text]  
  • McVoy, M. A., Nixon, D. E. (2005). Impact of 2-Bromo-5,6-Dichloro-1-{beta}-D-Ribofuranosyl Benzimidazole Riboside and Inhibitors of DNA, RNA, and Protein Synthesis on Human Cytomegalovirus Genome Maturation. J. Virol. 79: 11115-11127 [Abstract] [Full Text]  
  • Gershburg, E., Pagano, J. S. (2005). Epstein-Barr virus infections: prospects for treatment. J Antimicrob Chemother 56: 277-281 [Abstract] [Full Text]  
  • Gilbert, C., Boivin, G. (2005). Human Cytomegalovirus Resistance to Antiviral Drugs. Antimicrob. Agents Chemother. 49: 873-883 [Full Text]  
  • Kern, E. R., Kushner, N. L., Hartline, C. B., Williams-Aziz, S. L., Harden, E. A., Zhou, S., Zemlicka, J., Prichard, M. N. (2005). In Vitro Activity and Mechanism of Action of Methylenecyclopropane Analogs of Nucleosides against Herpesvirus Replication. Antimicrob. Agents Chemother. 49: 1039-1045 [Abstract] [Full Text]  
  • Gershburg, E., Marschall, M., Hong, K., Pagano, J. S. (2004). Expression and Localization of the Epstein-Barr Virus-Encoded Protein Kinase. J. Virol. 78: 12140-12146 [Abstract] [Full Text]  
  • Herget, T., Freitag, M., Morbitzer, M., Kupfer, R., Stamminger, T., Marschall, M. (2004). Novel Chemical Class of pUL97 Protein Kinase-Specific Inhibitors with Strong Anticytomegaloviral Activity. Antimicrob. Agents Chemother. 48: 4154-4162 [Abstract] [Full Text]  
  • Evers, D. L., Komazin, G., Ptak, R. G., Shin, D., Emmer, B. T., Townsend, L. B., Drach, J. C. (2004). Inhibition of Human Cytomegalovirus Replication by Benzimidazole Nucleosides Involves Three Distinct Mechanisms. Antimicrob. Agents Chemother. 48: 3918-3927 [Abstract] [Full Text]  
  • Chou, S., Marousek, G. I., Senters, A. E., Davis, M. G., Biron, K. K. (2004). Mutations in the Human Cytomegalovirus UL27 Gene That Confer Resistance to Maribavir. J. Virol. 78: 7124-7130 [Abstract] [Full Text]  
  • Underwood, M. R., Ferris, R. G., Selleseth, D. W., Davis, M. G., Drach, J. C., Townsend, L. B., Biron, K. K., Boyd, F. L. (2004). Mechanism of Action of the Ribopyranoside Benzimidazole GW275175X against Human Cytomegalovirus. Antimicrob. Agents Chemother. 48: 1647-1651 [Abstract] [Full Text]  
  • Kern, E. R., Hartline, C. B., Rybak, R. J., Drach, J. C., Townsend, L. B., Biron, K. K., Bidanset, D. J. (2004). Activities of Benzimidazole D- and L-Ribonucleosides in Animal Models of Cytomegalovirus Infections. Antimicrob. Agents Chemother. 48: 1749-1755 [Abstract] [Full Text]  
  • Gershburg, E., Hong, K., Pagano, J. S. (2004). Effects of Maribavir and Selected Indolocarbazoles on Epstein-Barr Virus Protein Kinase BGLF4 and on Viral Lytic Replication. Antimicrob. Agents Chemother. 48: 1900-1903 [Abstract] [Full Text]  
  • Nixon, D. E., McVoy, M. A. (2004). Dramatic Effects of 2-Bromo-5,6-Dichloro-1-{beta}-D-Ribofuranosyl Benzimidazole Riboside on the Genome Structure, Packaging, and Egress of Guinea Pig Cytomegalovirus. J. Virol. 78: 1623-1635 [Abstract] [Full Text]  
  • Komazin, G., Ptak, R. G., Emmer, B. T., Townsend, L. B., Drach, J. C. (2003). Resistance of Human Cytomegalovirus to the Benzimidazole L-Ribonucleoside Maribavir Maps to UL27. J. Virol. 77: 11499-11506 [Abstract] [Full Text]  
  • Krosky, P. M., Baek, M.-C., Jahng, W. J., Barrera, I., Harvey, R. J., Biron, K. K., Coen, D. M., Sethna, P. B. (2003). The Human Cytomegalovirus UL44 Protein Is a Substrate for the UL97 Protein Kinase. J. Virol. 77: 7720-7727 [Abstract] [Full Text]  
  • Williams, S. L., Hartline, C. B., Kushner, N. L., Harden, E. A., Bidanset, D. J., Drach, J. C., Townsend, L. B., Underwood, M. R., Biron, K. K., Kern, E. R. (2003). In Vitro Activities of Benzimidazole D- and L-Ribonucleosides against Herpesviruses. Antimicrob. Agents Chemother. 47: 2186-2192 [Abstract] [Full Text]  
  • De Clercq, E. (2003). New inhibitors of human cytomegalovirus (HCMV) on the horizon. J Antimicrob Chemother 51: 1079-1083 [Full Text]  
  • Wang, L. H., Peck, R. W., Yin, Y., Allanson, J., Wiggs, R., Wire, M. B. (2003). Phase I Safety and Pharmacokinetic Trials of 1263W94, a Novel Oral Anti-Human Cytomegalovirus Agent, in Healthy and Human Immunodeficiency Virus-Infected Subjects. Antimicrob. Agents Chemother. 47: 1334-1342 [Abstract] [Full Text]  
  • Selleseth, D. W., Talarico, C. L., Miller, T., Lutz, M. W., Biron, K. K., Harvey, R. J. (2003). Interactions of 1263W94 with Other Antiviral Agents in Inhibition of Human Cytomegalovirus Replication. Antimicrob. Agents Chemother. 47: 1468-1471 [Abstract] [Full Text]  
  • Thomsen, D. R., Oien, N. L., Hopkins, T. A., Knechtel, M. L., Brideau, R. J., Wathen, M. W., Homa, F. L. (2003). Amino Acid Changes within Conserved Region III of the Herpes Simplex Virus and Human Cytomegalovirus DNA Polymerases Confer Resistance to 4-Oxo-Dihydroquinolines, a Novel Class of Herpesvirus Antiviral Agents. J. Virol. 77: 1868-1876 [Abstract] [Full Text]  
  • Krosky, P. M., Baek, M.-C., Coen, D. M. (2002). The Human Cytomegalovirus UL97 Protein Kinase, an Antiviral Drug Target, Is Required at the Stage of Nuclear Egress. J. Virol. 77: 905-914 [Abstract] [Full Text]  
  • Baek, M.-C., Krosky, P. M., Coen, D. M. (2002). Relationship between Autophosphorylation and Phosphorylation of Exogenous Substrates by the Human Cytomegalovirus UL97 Protein Kinase. J. Virol. 76: 11943-11952 [Abstract] [Full Text]  
  • Koszalka, G. W., Johnson, N. W., Good, S. S., Boyd, L., Chamberlain, S. C., Townsend, L. B., Drach, J. C., Biron, K. K. (2002). Preclinical and Toxicology Studies of 1263W94, a Potent and Selective Inhibitor of Human Cytomegalovirus Replication. Antimicrob. Agents Chemother. 46: 2373-2380 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»