Inhibition of herpesvirus replication by 5-substituted 4'-thiopyrimidine nucleosides.
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 (EC(50)s) of 0.1, 0.5, and 2 microM, respectively. It also inhibited the replication of human cytomegalovirus (HCMV) with an EC(50) of 5.9 microM 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 (EC(50)s of 4 to 12 microM) 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.
Prichard
Mark N
MN
Department of Pediatrics, University of Alabama School of Medicine, Birmingham, AL 35233, USA. mprichard@peds.uab.edu
Quenelle
Debra C
DC
Hartline
Caroll B
CB
Harden
Emma A
EA
Jefferson
Geraldine
G
Frederick
Samuel L
SL
Daily
Shannon L
SL
Whitley
Richard J
RJ
Tiwari
Kamal N
KN
Maddry
Joseph A
JA
Secrist
John A
JA
Kern
Earl R
ER
D000818:Animals; D000998:Antiviral Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000502:physiology; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D019084:Fluorescent Antibody Technique, Indirect; D006564:Herpesviridae / Q000187:drug effects* / Q000235:genetics; D006566:Herpesviridae Infections / Q000188:drug therapy* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000235:genetics; D018258:Herpesvirus 2, Human / Q000187:drug effects / Q000235:genetics; D015654:Herpesvirus 6, Human / Q000187:drug effects / Q000235:genetics; D019288:Herpesvirus 8, Human / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D011741:Pyrimidine Nucleosides; D014764:Viral Proteins; D004259:DNA-Directed DNA Polymerase