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Antimicrobial Agents and Chemotherapy, May 2004, p. 1647-1651, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1647-1651.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Mechanism of Action of the Ribopyranoside Benzimidazole GW275175X against Human Cytomegalovirus

Mark R. Underwood,1* Robert G. Ferris,2 Dean W. Selleseth,2 Michelle G. Davis,1 John C. Drach,3 Leroy B. Townsend,4 Karen K. Biron,1 and F. Leslie Boyd5

Departments of International Clinical Virology,1 Virology,2 Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, North Carolina 27709,5 Department of Biologic and Materials Sciences, School of Dentistry,3 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 481094

Received 22 August 2003/ Returned for modification 13 November 2003/ Accepted 21 January 2004

New human cytomegalovirus (HCMV) therapies with novel mechanisms of action are needed to treat drug-resistant HCMV that arises during therapy with currently approved agents. 2-Bromo-5,6-dichloro-1-ß-D-ribofuranosyl-1H-benzimidazole (BDCRB) is an effective anti-HCMV agent with a novel mechanism of action, but problems with in vivo stability preclude clinical development. A D-ribopyranosyl derivative of BDCRB, GW275175X, displays similar antiviral activity without the in vivo stability problems. We present an initial description of the activity of GW275175X against HCMV, other herpesviruses, and selected nonherpesviruses. In addition, we show that it acts as a DNA maturation inhibitor like the parent compound, BDCRB, rather than via the mechanisms of action of 1263W94 or any anti-HCMV drugs approved for marketing. GW275175X is a promising candidate for clinical development as an anti-HCMV agent.

* Corresponding author. Mailing address: Department of International Clinical Virology, GlaxoSmithKline, Five Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709. Phone: (919) 483-9151. Fax: (919) 315-5243. E-mail: mark.r.underwood{at}gsk.com.

Antimicrobial Agents and Chemotherapy, May 2004, p. 1647-1651, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1647-1651.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Wang, J. B., McVoy, M. A. (2008). Mutagenesis of the murine cytomegalovirus M56 terminase gene. J. Gen. Virol. 89: 2864-2868 [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]  
  • Gilbert, C., Boivin, G. (2005). Human Cytomegalovirus Resistance to Antiviral Drugs. Antimicrob. Agents Chemother. 49: 873-883 [Full Text]  


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