HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Broad-spectrum antiviral activity of the acyclic guanosine phosphonate (R,S)-HPMPG.

Abstract
(R,S)-9-(3-hydroxy-2-phosphonomethoxypropyl)guanine [(R,S)-HPMPG] exhibits broad spectrum antiviral activity with an ED50 of less than 1 microM against herpes simplex virus (HSV) types 1 and 2, varicella zoster virus, human cytomegalovirus (HCMV) and vaccinia in plaque reduction assays. Wild type HSV-2 and its thymidine kinase deficient variant are equally sensitive to (R,S)-HPMPG. (R,S)-HPMPG is 100-fold more potent than acyclovir (ED50 = 0.45 microM vs. 44 microM, respectively) against HCMV in cell culture, and 10-fold more active than acyclovir in extending survival time in mice intraperitoneally infected with 70 LD50 HSV-1. However, (R,S)-HPMPG is toxic when administered repeatedly at 44 mg/kg/day in uninfected adult mice. The diphosphoryl derivative of HPMPG was enzymatically synthesized and is a competitive inhibitor of HSV-1 DNA polymerase relative to dGTP (K1 = 0.03 microM). HPMPG-PP is 70-fold less active at inhibiting HeLa DNA polymerase alpha than HSV-1 DNA polymerase. At concentrations between 0.3 and 1.5 microM (R,S)-HPMPG inhibited HSV-1 DNA replication greater than or equal to 50% in infected cells as measured by nucleic acid hybridization. Consistent with inhibition of viral DNA synthesis, 6 to 30 microM (R,S)-HPMPG reduces late viral polypeptide synthesis in HSV-1 infected cells. These data indicate that (R,S)-HPMPG is a thymidine kinase independent broad spectrum antiviral drug which is capable of inhibiting viral DNA polymerase.
AuthorsB J Terry, K E Mazina, A V Tuomari, M L Haffey, M Hagen, A Feldman, W A Slusarchyk, M G Young, R Zahler, A K Field
JournalAntiviral research (Antiviral Res) Vol. 10 Issue 4-5 Pg. 235-51 (Dec 01 1988) ISSN: 0166-3542 [Print] Netherlands
PMID2852486 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • Antiviral Agents
  • DNA, Viral
  • Nucleic Acid Synthesis Inhibitors
  • Organophosphorus Compounds
  • Viral Proteins
  • 9-(3-hydroxy-2-phosphonomethoxypropyl)guanine
  • Guanine
  • Ganciclovir
  • Acyclovir
Topics
  • Acyclovir (analogs & derivatives, pharmacology)
  • Animals
  • Antiviral Agents (chemical synthesis, pharmacology, therapeutic use, toxicity)
  • Cell Line
  • Cytomegalovirus (drug effects)
  • DNA Replication (drug effects)
  • DNA Viruses (drug effects)
  • DNA, Viral (biosynthesis, drug effects)
  • Female
  • Ganciclovir
  • Guanine (analogs & derivatives, chemical synthesis, pharmacology, therapeutic use, toxicity)
  • HeLa Cells
  • Herpes Simplex (drug therapy)
  • Herpesvirus 3, Human (drug effects)
  • Mice
  • Molecular Structure
  • Nucleic Acid Synthesis Inhibitors
  • Organophosphorus Compounds
  • Simplexvirus (drug effects)
  • Vaccinia virus (drug effects)
  • Vero Cells
  • Viral Proteins (biosynthesis)
  • Virus Replication (drug effects)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: