Inhibition of Herpesvirus Replication by 5-Substituted 4′-Thiopyrimidine Nucleosides ▿
AUTOR(ES)
Prichard, Mark N.
FONTE
American Society for Microbiology (ASM)
RESUMO
A series of 4′-thionucleosides were synthesized and evaluated for activities against orthopoxviruses and herpesviruses. We reported previously that one analog, 5-iodo-4′-thio-2′-deoxyuridine (4′-thioIDU), exhibits good activity both in vitro and in vivo against two orthopoxviruses. This compound also has good activity in cell culture against many of the herpesviruses. It inhibited the replication of herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus with 50% effective concentrations (EC50s) of 0.1, 0.5, and 2 μM, respectively. It also inhibited the replication of human cytomegalovirus (HCMV) with an EC50 of 5.9 μM but did not selectively inhibit Epstein-Barr virus, human herpesvirus 6, or human herpesvirus 8. While acyclovir-resistant strains of HSV-1 and HSV-2 were comparatively resistant to 4′-thioIDU, it retained modest activity (EC50s of 4 to 12 μM) against these strains. Some ganciclovir-resistant strains of HCMV also exhibited reduced susceptibilities to the compound, which appeared to be related to the specific mutations in the DNA polymerase, consistent with the observed incorporation of the compound into viral DNA. The activity of 4′-thioIDU was also evaluated using mice infected intranasally with the MS strain of HSV-2. Although there was no decrease in final mortality rates, the mean length of survival after inoculation increased significantly (P < 0.05) for all animals receiving 4′-thioIDU. The findings from the studies presented here suggest that 4′-thioIDU is a good inhibitor of some herpesviruses, as well as orthopoxviruses, and this class of compounds warrants further study as a therapy for infections with these viruses.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2786333Documentos Relacionados
- Anti-herpes simplex virus activity of 5-substituted 2-pyrimidinone nucleosides.
- INHIBITION OF A THYMINE-DEFICIENT MUTANT OF ESCHERICHIA COLI BY 5-SUBSTITUTED URACILS
- On the conformation of 5-substituted uridines as studied by proton magnetic resonance.
- Possible molecular basis for antiviral activity of certain 5-substituted deoxyuridines.
- Stereoselective addition of chiral titanium enolates to 5-substituted five-membered oxocarbenium ions