Susceptibilities of several clinical varicella-zoster virus (VZV) isolates and drug-resistant VZV strains to bicyclic furano pyrimidine nucleosides.
Varicella-zoster virus (VZV) is responsible for primary infections as well as reactivations after latency in the dorsal root ganglia. The treatment of such infections is mandatory for immunocompromised patients and highly recommended for elderly patients with herpes zoster infections (also called zona or shingles). The treatment of choice is presently based on four molecules, acyclovir (ACV), valaciclovir, famciclovir, and (in Europe) brivudine (BVDU). We present here our data on the antiviral activity of a new class of potent and selective anti-VZV compounds, bicylic pyrimidine nucleoside analogues (BCNAs), against a broad variety of clinical isolates and different drug-resistant virus strains. The results show that the BCNAs are far more potent inhibitors than ACV and BVDU against clinical VZV isolates as well as the VZV reference strains Oka and YS. The BCNAs were not active against ACV- and BVDU-resistant VZV strains bearing mutations in the viral thymidine kinase gene but kept their inhibitory potential against virus strains with mutations in the VZV DNA polymerase gene. Mutant virus strains selected in the presence of the BCNAs were solely cross-resistant to drugs, such as ACV and BVDU, that depend for their antiviral action on metabolic activation by the viral thymidine kinase.
Andrei
Graciela
G
Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium. graciela.andrei@rega.kuleuven.ac.be
Sienaert
Rebecca
R
McGuigan
Chris
C
De Clercq
Erik
E
Balzarini
Jan
J
Snoeck
Robert
R
D015075:2-Aminopurine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000212:Acyclovir / Q000031:analogs & derivatives* / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D024882:Drug Resistance, Viral; D000077595:Famciclovir; D014645:Herpesvirus 3, Human / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009705:Nucleosides / Q000494:pharmacology*; D000077483:Valacyclovir; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000998:Antiviral Agents; D009705:Nucleosides; C020235:brivudine; D015075:2-Aminopurine; D001973:Bromodeoxyuridine; D014633:Valine; D000077483:Valacyclovir; D000077595:Famciclovir; D000212:Acyclovir
Eur J Clin Microbiol Infect Dis. 1995 Apr;14(4):318-29
7649195
J Med Virol. 1994 Apr;42(4):338-47
8046424
J Med Chem. 1999 Nov 4;42(22):4479-84
10579812
Expert Opin Investig Drugs. 2000 Aug;9(8):1743-51
11060773
J Med Chem. 2000 Dec 28;43(26):4993-7
11150169
Mol Pharmacol. 2002 Feb;61(2):249-54
11809847
Mol Pharmacol. 2002 May;61(5):1140-5
11961132
Biochim Biophys Acta. 2002 Jul 18;1587(2-3):287-95
12084470
J Antimicrob Chemother. 2002 Jul;50(1):5-9
12096000
J Virol. 2003 Feb;77(4):2349-58
12551972
Clin Cancer Res. 2003 Mar;9(3):976-80
12631595
J Clin Virol. 2003 Apr;26(3):277-89; discussion 291-3
12637076
Commun Dis Public Health. 2003 Apr;6(1):59-62
12736975
Antimicrob Agents Chemother. 2003 Jul;47(7):2186-92
12821466
Antiviral Res. 2003 Jun;59(1):49-56
12834860
Drugs Today (Barc). 2003 May;39(5):359-71
12861349
J Pediatr Gastroenterol Nutr. 2003 Aug;37(2):183-6
12883306
Transplant Proc. 2003 Aug;35(5):1758-9
12962784
J Infect Dis. 2003 Oct 1;188(7):948-53
14513412
J Infect Dis. 2003 Oct 1;188(7):954-9
14513413
Nucleosides Nucleotides Nucleic Acids. 2003 May-Aug;22(5-8):995-7
14565329
Biochem Biophys Res Commun. 2004 Mar 19;315(4):877-83
14985094
Antiviral Res. 2004 Mar;61(3):181-7
15168799
Drugs. 1999 Feb;57(2):187-206
10188760