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 Underwood, M. R.
Right arrow Articles by Biron, K. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Underwood, M. R.
Right arrow Articles by Biron, K. K.

 Previous Article  |  Next Article 

J Virol, January 1998, p. 717-725, Vol. 72, No. 1
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Inhibition of Human Cytomegalovirus DNA Maturation by a Benzimidazole Ribonucleoside Is Mediated through the UL89 Gene Product

Mark R. Underwood,1,* Robert J. Harvey,1 Sylvia C. Stanat,1 Mary Lou Hemphill,1 Teresa Miller,1 John C. Drach,2,3 Leroy B. Townsend,3 and Karen K. Biron1

Department of Virology, Glaxo Wellcome Inc., Research Triangle Park, North Carolina 27709,1 and Department of Biologic and Materials Sciences, School of Dentistry,2 and Department of Medicinal Chemistry, College of Pharmacy,3 University of Michigan, Ann Arbor, Michigan 48109

Received 2 September 1997/Accepted 10 October 1997

2-Bromo-5,6-dichloro-1-beta -D-ribofuranosyl benzimidazole (BDCRB) is a member of a new class of benzimidazole ribonucleosides which inhibit human cytomegalovirus (HCMV) late in the replication cycle without inhibiting viral DNA synthesis. We show here that polygenomic concatemeric HCMV DNA does not mature to unit genome length in the presence of BDCRB. To discover the locus of action, virus resistant to BDCRB was selected by serial passage in the presence of the compound. Genetic mapping experiments with BDCRB-resistant virus demonstrated that the resistance phenotype mapped to one amino acid (Asp344Glu; low resistance) or two amino acids (Asp344Glu and Ala355Thr; high resistance) within the product of exon 2 of the HCMV UL89 open reading frame. The HCMV UL89 open reading frame and its homologs are among the most conserved open reading frames in the herpesviruses, and their products have sequence similarities to a known ATP-dependent endonuclease from the double-stranded DNA bacteriophage T4. These findings strongly suggest that BDCRB prevents viral DNA maturation by interacting with a UL89 gene product and that the UL89 open reading frame may encode an endonucleolytic subunit of the putative HCMV terminase. Further, since mammalian cell DNA replication does not involve a DNA maturation step, compounds which inhibit viral DNA maturation should be selective and safe.

* Corresponding author. Mailing address: Department of Virology, Glaxo Wellcome Inc., P.O. Box 13398, Research Triangle Park, NC 27709-3398. Phone: (919) 483-9151. Fax: (919) 315-5243. E-mail: mru43326{at}glaxowellcome.com.




This article has been cited by other articles:

  • Hwang, J.-S., Schilf, R., Drach, J. C., Townsend, L. B., Bogner, E. (2009). Susceptibilities of Human Cytomegalovirus Clinical Isolates and Other Herpesviruses to New Acetylated, Tetrahalogenated Benzimidazole D-Ribonucleosides. Antimicrob. Agents Chemother. 53: 5095-5101 [Abstract] [Full Text]  
  • Tandon, R., AuCoin, D. P., Mocarski, E. S. (2009). Human Cytomegalovirus Exploits ESCRT Machinery in the Process of Virion Maturation. J. Virol. 83: 10797-10807 [Abstract] [Full Text]  
  • Cockrell, S. K., Sanchez, M. E., Erazo, A., Homa, F. L. (2009). Role of the UL25 Protein in Herpes Simplex Virus DNA Encapsidation. J. Virol. 83: 47-57 [Abstract] [Full Text]  
  • Wang, J. B., McVoy, M. A. (2008). Mutagenesis of the murine cytomegalovirus M56 terminase gene. J. Gen. Virol. 89: 2864-2868 [Abstract] [Full Text]  
  • Tandon, R., Mocarski, E. S. (2008). Control of Cytoplasmic Maturation Events by Cytomegalovirus Tegument Protein pp150. J. Virol. 82: 9433-9444 [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]  
  • Seo, J.-Y., Britt, W. J. (2006). Sequence Requirements for Localization of Human Cytomegalovirus Tegument Protein pp28 to the Virus Assembly Compartment and for Assembly of Infectious Virus.. J. Virol. 80: 5611-5626 [Abstract] [Full Text]  
  • Wang, J., Loveland, A. N., Kattenhorn, L. M., Ploegh, H. L., Gibson, W. (2006). High-Molecular-Weight Protein (pUL48) of Human Cytomegalovirus Is a Competent Deubiquitinating Protease: Mutant Viruses Altered in Its Active-Site Cysteine or Histidine Are Viable.. J. Virol. 80: 6003-6012 [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]  
  • Dittmer, A., Drach, J. C., Townsend, L. B., Fischer, A., Bogner, E. (2005). Interaction of the Putative Human Cytomegalovirus Portal Protein pUL104 with the Large Terminase Subunit pUL56 and Its Inhibition by Benzimidazole-D-Ribonucleosides. J. Virol. 79: 14660-14667 [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]  
  • Lorenzi, P. L., Landowski, C. P., Song, X., Borysko, K. Z., Breitenbach, J. M., Kim, J. S., Hilfinger, J. M., Townsend, L. B., Drach, J. C., Amidon, G. L. (2005). Amino Acid Ester Prodrugs of 2-Bromo-5,6-dichloro-1-({beta}-D-ribofuranosyl)benzimidazole Enhance Metabolic Stability in Vitro and in Vivo. J. Pharmacol. Exp. Ther. 314: 883-890 [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]  
  • North, T. W., Sequar, G., Townsend, L. B., Drach, J. C., Barry, P. A. (2004). Rhesus Cytomegalovirus Is Similar to Human Cytomegalovirus in Susceptibility to Benzimidazole Nucleosides. Antimicrob. Agents Chemother. 48: 2760-2765 [Abstract] [Full Text]  
  • Fryer, J. F. L., Griffiths, P. D., Emery, V. C., Clark, D. A. (2004). Susceptibility of porcine cytomegalovirus to antiviral drugs. J Antimicrob Chemother 53: 975-980 [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]  
  • 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., Townsend, L. B., Drach, J. C. (2004). Role of a Mutation in Human Cytomegalovirus Gene UL104 in Resistance to Benzimidazole Ribonucleosides. J. Virol. 78: 710-715 [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]  
  • 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]  
  • 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]  
  • Scholz, B., Rechter, S., Drach, J. C., Townsend, L. B., Bogner, E. (2003). Identification of the ATP-binding site in the terminase subunit pUL56 of human cytomegalovirus. Nucleic Acids Res 31: 1426-1433 [Abstract] [Full Text]  
  • Visalli, R. J., Fairhurst, J., Srinivas, S., Hu, W., Feld, B., DiGrandi, M., Curran, K., Ross, A., Bloom, J. D., van Zeijl, M., Jones, T. R., O'Connell, J., Cohen, J. I. (2003). Identification of Small Molecule Compounds That Selectively Inhibit Varicella-Zoster Virus Replication. J. Virol. 77: 2349-2358 [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]  
  • Biron, K. K., Harvey, R. J., Chamberlain, S. C., Good, S. S., Smith, A. A. III, Davis, M. G., Talarico, C. L., Miller, W. H., Ferris, R., Dornsife, R. E., Stanat, S. C., Drach, J. C., Townsend, L. B., Koszalka, G. W. (2002). Potent and Selective Inhibition of Human Cytomegalovirus Replication by 1263W94, a Benzimidazole L-Riboside with a Unique Mode of Action. Antimicrob. Agents Chemother. 46: 2365-2372 [Abstract] [Full Text]  
  • Scheffczik, H., Savva, C. G. W., Holzenburg, A., Kolesnikova, L., Bogner, E. (2002). The terminase subunits pUL56 and pUL89 of human cytomegalovirus are DNA-metabolizing proteins with toroidal structure. Nucleic Acids Res 30: 1695-1703 [Abstract] [Full Text]  
  • Hwang, J.-S., Bogner, E. (2002). ATPase Activity of the Terminase Subunit pUL56 of Human Cytomegalovirus. J. Biol. Chem. 277: 6943-6948 [Abstract] [Full Text]  
  • Krosky, P. M., Borysko, K. Z., Nassiri, M. R., Devivar, R. V., Ptak, R. G., Davis, M. G., Biron, K. K., Townsend, L. B., Drach, J. C. (2002). Phosphorylation of {beta}-D-Ribosylbenzimidazoles Is Not Required for Activity against Human Cytomegalovirus. Antimicrob. Agents Chemother. 46: 478-486 [Abstract] [Full Text]  
  • Gershburg, E., Pagano, J. S. (2002). 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. J. Virol. 76: 998-1003 [Abstract] [Full Text]  
  • Reefschlaeger, J., Bender, W., Hallenberger, S., Weber, O., Eckenberg, P., Goldmann, S., Haerter, M., Buerger, I., Trappe, J., Herrington, J. A., Haebich, D., Ruebsamen-Waigmann, H. (2001). Novel non-nucleoside inhibitors of cytomegaloviruses (BAY 38-4766): in vitro and in vivo antiviral activity and mechanism of action. J Antimicrob Chemother 48: 757-767 [Abstract] [Full Text]  
  • McSharry, J. J., McDonough, A., Olson, B., Talarico, C., Davis, M., Biron, K. K. (2001). Inhibition of Ganciclovir-Susceptible and -Resistant Human Cytomegalovirus Clinical Isolates by the Benzimidazole L-Riboside 1263W94. CVI 8: 1279-1281 [Abstract] [Full Text]  
  • McSharry, J. J., McDonough, A., Olson, B., Hallenberger, S., Reefschlaeger, J., Bender, W., Drusano, G. L. (2001). Susceptibilities of Human Cytomegalovirus Clinical Isolates to BAY38-4766, BAY43-9695, and Ganciclovir. Antimicrob. Agents Chemother. 45: 2925-2927 [Abstract] [Full Text]  
  • Buerger, I., Reefschlaeger, J., Bender, W., Eckenberg, P., Popp, A., Weber, O., Graeper, S., Klenk, H.-D., Ruebsamen-Waigmann, H., Hallenberger, S. (2001). A Novel Nonnucleoside Inhibitor Specifically Targets Cytomegalovirus DNA Maturation via the UL89 and UL56 Gene Products. J. Virol. 75: 9077-9086 [Abstract] [Full Text]  
  • Wolf, D. G., Courcelle, C. T., Prichard, M. N., Mocarski, E. S. (2001). Distinct and separate roles for herpesvirus-conserved UL97 kinase in cytomegalovirus DNA synthesis and encapsidation. Proc. Natl. Acad. Sci. USA 98: 1895-1900 [Abstract] [Full Text]  
  • Sheaffer, A. K., Newcomb, W. W., Gao, M., Yu, D., Weller, S. K., Brown, J. C., Tenney, D. J. (2001). Herpes Simplex Virus DNA Cleavage and Packaging Proteins Associate with the Procapsid prior to Its Maturation. J. Virol. 75: 687-698 [Abstract] [Full Text]  
  • Abbotts, A. P., Preston, V. G., Hughes, M., Patel, A. H., Stow, N. D. (2000). Interaction of the herpes simplex virus type 1 packaging protein UL15 with full-length and deleted forms of the UL28 protein. J. Gen. Virol. 81: 2999-3009 [Abstract] [Full Text]  
  • van Zeijl, M., Fairhurst, J., Jones, T. R., Vernon, S. K., Morin, J., LaRocque, J., Feld, B., O'Hara, B., Bloom, J. D., Johann, S. V. (2000). Novel Class of Thiourea Compounds That Inhibit Herpes Simplex Virus Type 1 DNA Cleavage and Encapsidation: Resistance Maps to the UL6 Gene. J. Virol. 74: 9054-9061 [Abstract] [Full Text]  
  • Marschall, M., Freitag, M., Weiler, S., Sorg, G., Stamminger, T. (2000). Recombinant Green Fluorescent Protein-Expressing Human Cytomegalovirus as a Tool for Screening Antiviral Agents. Antimicrob. Agents Chemother. 44: 1588-1597 [Abstract] [Full Text]  
  • Zacny, V. L., Gershburg, E., Davis, M. G., Biron, K. K., Pagano, J. S. (1999). 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. J. Virol. 73: 7271-7277 [Abstract] [Full Text]  
  • Koslowski, K. M., Shaver, P. R., Casey, J. T. II, Wilson, T., Yamanaka, G., Sheaffer, A. K., Tenney, D. J., Pederson, N. E. (1999). Physical and Functional Interactions between the Herpes Simplex Virus UL15 and UL28 DNA Cleavage and Packaging Proteins. J. Virol. 73: 1704-1707 [Abstract] [Full Text]  
  • Krosky, P. M., Underwood, M. R., Turk, S. R., Feng, K. W.-H., Jain, R. K., Ptak, R. G., Westerman, A. C., Biron, K. K., Townsend, L. B., Drach, J. C. (1998). Resistance of Human Cytomegalovirus to Benzimidazole Ribonucleosides Maps to Two Open Reading Frames: UL89 and UL56. J. Virol. 72: 4721-4728 [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»