Broad-spectrum antiviral activity of the acyclic guanosine phosphonate (R,S)-HPMPG.
(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.
Terry
B J
BJ
Microbial Biochemistry, Squibb Institute for Medical Research, Princeton, New Jersey 08540.
Mazina
K E
KE
Tuomari
A V
AV
Haffey
M L
ML
Hagen
M
M
Feldman
A
A
Slusarchyk
W A
WA
Young
M G
MG
Zahler
R
R
Field
A K
AK
D000212:Acyclovir / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004267:DNA Viruses / Q000187:drug effects*; D004279:DNA, Viral / Q000096:biosynthesis / Q000187:drug effects; D005260:Female; D015774:Ganciclovir; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D006367:HeLa Cells; D006561:Herpes Simplex / Q000188:drug therapy*; D014645:Herpesvirus 3, Human / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D019384:Nucleic Acid Synthesis Inhibitors; D009943:Organophosphorus Compounds; D018139:Simplexvirus / Q000187:drug effects; D014616:Vaccinia virus / Q000187:drug effects; D014709:Vero Cells; D014764:Viral Proteins / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004279:DNA, Viral; D019384:Nucleic Acid Synthesis Inhibitors; D009943:Organophosphorus Compounds; D014764:Viral Proteins; C058654:9-(3-hydroxy-2-phosphonomethoxypropyl)guanine; D006147:Guanine; D015774:Ganciclovir; D000212:Acyclovir