Inhibition of human cytomegalovirus replication by benzimidazole nucleosides involves three distinct mechanisms

Antimicrobial Agents and Chemotherapy
David L EversJohn C Drach

Abstract

The benzimidazole nucleosides 2-bromo-5,6-dichloro-1-(beta-d-ribofuranosyl)benzimidazole (BDCRB) and 2-isopropylamino-5,6-dichloro-1-(beta-l-ribofuranosyl)benzimidazole (1263W94, or maribavir) are potent and selective inhibitors of human cytomegalovirus (HCMV) replication. These inhibitors act by two different mechanisms: BDCRB blocks the processing and maturation of viral DNA, whereas maribavir prevents viral DNA synthesis and capsid nuclear egress. In order to determine by which of these two mechanisms other benzimidazole nucleosides acted, we performed time-of-addition studies and other experiments with selected new analogs. We found that the erythrofuranosyl analog and the alpha-lyxofuranosyl analog acted late in the viral replication cycle, similar to BDCRB. In marked contrast, the alpha-5'-deoxylyxofuranosyl analog of 2,5,6-trichloro-1-(beta-d-ribofuranosyl)benzimidazole (compound UMJD1311) acted early in the replication cycle, too early to be consistent with either mechanism. Similar to other reports on early acting inhibitors of herpesviruses, compound 1311 was multiplicity of infection dependent, an observation that could not be reproduced with UV-inactivated virus. HCMV isolates resistant to BDCRB and maribavir were s...Continue Reading

References

Mar 1, 1979·Archives of Internal Medicine·H H Balfour
Jun 11, 1991·Antimicrobial Agents and Chemotherapy·M N PrichardC Shipman
Oct 1, 1990·Antiviral Research·M N Prichard, C Shipman
Jan 1, 1990·Current Topics in Microbiology and Immunology·M S CheeJ A Martignetti
Jan 1, 1989·American Journal of Nephrology·G DerayM Gentilini
Apr 1, 1987·Antimicrobial Agents and Chemotherapy·S R TurkJ C Drach
Jan 1, 1969·Proceedings of the Society for Experimental Biology and Medicine·C Shipman
Jan 1, 1994·Clinical Microbiology Reviews·A K Field, K K Biron
Aug 29, 1996·The New England Journal of Medicine·Y F ZhouS E Epstein
Sep 5, 1996·The New England Journal of Medicine·C S Crumpacker
Jun 10, 1997·Proceedings of the National Academy of Sciences of the United States of America·J W CritchfieldS T Butera
Apr 8, 1999·Drugs·C M Perry, J A Balfour
Apr 9, 1999·Clinical Microbiology Reviews·A Erice
Aug 3, 1999·Antimicrobial Agents and Chemotherapy·J G JacobsonJ C Drach
Jul 6, 2000·Journal of Medicinal Chemistry·K S GudmundssonL B Townsend
Feb 15, 2001·Proceedings of the National Academy of Sciences of the United States of America·D G WolfE S Mocarski
Jun 8, 2001·Proceedings of the National Academy of Sciences of the United States of America·K A SimmenK Früh
Jul 24, 2001·Drugs·M Curran, S Noble
Jan 18, 2002·Antimicrobial Agents and Chemotherapy·Paula M KroskyJohn C Drach
Feb 22, 2003·Nucleic Acids Research·Brigitte ScholzElke Bogner

❮ Previous
Next ❯

Citations

Mar 16, 2011·Chemical Reviews·Jonas J Forsman, Reko Leino
Jun 14, 2006·International Ophthalmology Clinics·Torsten W Wiegand, Lucy H Y Young
Jul 3, 2013·Antimicrobial Agents and Chemotherapy·Brian G GentryJohn C Drach
Mar 5, 2008·Antimicrobial Agents and Chemotherapy·D Ronald GoldwaterStephen A Villano
Mar 2, 2013·Journal of Virology·Christopher B WhitehurstJoseph S Pagano
Apr 4, 2007·Expert Review of Anti-infective Therapy·Scott T Rottinghaus, Richard J Whitley
Aug 19, 2005·Expert Review of Anti-infective Therapy·Eric Denes, Sylvie Ranger-Rogez
Mar 3, 2015·Viruses·Ritesh TandonJames F Conway
Sep 3, 2011·Expert Opinion on Drug Metabolism & Toxicology·Alistair McGregor, K Yeon Choi
Feb 25, 2009·Expert Opinion on Pharmacotherapy·Andreas SchreiberDetlef Michel
May 8, 2007·Bioorganic & Medicinal Chemistry·Kristina StarcevićGrace Karminski-Zamola
Nov 21, 2007·Reviews in Medical Virology·Beatrice MercorelliGiorgio Palù
Aug 5, 2010·Transplant Infectious Disease : an Official Journal of the Transplantation Society·R K AveryS Villano
Jul 3, 2007·The American Journal of Medicine·Robert C MoelleringLawrence Corey
Nov 6, 2007·American Journal of Infection Control·Robert C MoelleringUNKNOWN American Society for Microbiology
Jul 19, 2014·Current Opinion in Virology·Scott H James, Mark N Prichard
Mar 17, 2012·Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology·Kathy K LiCelia Aitken

❮ Previous
Next ❯

Related Concepts

Related Feeds

Anthelmintics

Anthelmintics or antihelminthics are a group of antiparasitic drugs that expel parasitic worms (helminths) and other internal parasites from the body by either stunning or killing them and without causing significant damage to the host. Discover the latest research on anthelmintics here.

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

CRISPR Screens in Drug Resistance

CRISPR-Cas system enables the editing of genes to create or correct mutations. This feed focuses on the application of CRISPR-Cas system in high-throughput genome-wide screens to identify genes that may confer drug resistance.

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Related Papers

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences
Mariola AndrzejewskaZygmunt Kazimierczuk
European Journal of Medicinal Chemistry
Gabriel Navarrete-VázquezFrancisco Hernández-Luis
© 2021 Meta ULC. All rights reserved