Broad-spectrum antiviral activity of the acyclic guanosine phosphonate (R,S)-HPMPG
| Autor: | Tuomari Av, Robert Zahler, Terry Bj, Feldman A, A K Field, M. E. Hagen, Slusarchyk Wa, M.G. Young, Mazina Ke, M L Haffey |
|---|---|
| Rok vydání: | 1988 |
| Předmět: |
DNA Replication
Herpesvirus 3 Human Guanine DNA polymerase viruses Acyclovir Cytomegalovirus Vaccinia virus medicine.disease_cause Virus Replication Antiviral Agents Virus Cell Line Nucleic acid thermodynamics chemistry.chemical_compound Mice Viral Proteins Organophosphorus Compounds Virology medicine Animals Simplexvirus Ganciclovir Vero Cells Polymerase Nucleic Acid Synthesis Inhibitors Pharmacology biology Molecular Structure DNA replication DNA Viruses Herpes Simplex Herpes simplex virus chemistry Thymidine kinase DNA Viral biology.protein Female HeLa Cells |
| Zdroj: | Antiviral research. 10(4-5) |
| ISSN: | 0166-3542 |
| Popis: | (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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|