Mechanism of action of the ribopyranoside benzimidazole GW275175X against human cytomegalovirus.
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-beta-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.
Underwood
Mark R
MR
Department of International Clinical Virology, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. mark.r.underwood@gsk.com
Ferris
Robert G
RG
Selleseth
Dean W
DW
Davis
Michelle G
MG
Drach
John C
JC
Townsend
Leroy B
LB
Biron
Karen K
KK
Boyd
F Leslie
FL
D000998:Antiviral Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects*; D004247:DNA / Q000235:genetics; D004586:Electrophoresis; D006564:Herpesviridae / Q000187:drug effects; D006801:Humans; D017403:In Situ Hybridization; D007202:Indicators and Reagents; D012263:Ribonucleosides / Q000494:pharmacology*; D010948:Viral Plaque Assay
C486447:2-bromo-5,6-dichloro-1-ribopyranosyl-1H-benzimidazole; D000998:Antiviral Agents; D001562:Benzimidazoles; D007202:Indicators and Reagents; D012263:Ribonucleosides; D004247:DNA