ABSTRACT
Aliphatic and aromatic mono-, di-, and triesters of phosphonoformic acid (foscarnet) were synthesized. The triesters were prepared by the Michaelis-Arbuzov reaction and were hydrolyzed to di- and monoesters. The compounds were tested for antiviral activity on isolated herpes simplex virus type 1 (HSV-1) DNA polymerase, in a HSV-1 plaque reduction assay, and on a cutaneous HSV-1 infection in guinea pigs. None of the esters inhibited the activity of isolated HSV-1 polymerases. Monoesters with a free carboxylic group and diesters with an aromatic carboxylic ester function were active against the cutaneous herpes infection. Mono- and diesters with an aromatic phosphonic ester group also showed activity in the plaque-reduction assay. However, mono- and diesters with an aromatic phosphonic ester group also showed activity in the plaque-reduction assay. However, mono- and diesters with aliphatic carboxylic ester groups were inactive in all test systems. The results show that all three acidic groups of phosphonoformic acid must be free in order to get antiviral activity at the enzyme level. However, certain esters of this acid may be biotransformed to the acid itself to give antiherpes activity.
Subject(s)
Antiviral Agents/chemical synthesis , Organophosphorus Compounds/chemical synthesis , Phosphonoacetic Acid , Phosphonoacetic Acid/chemical synthesis , Simplexvirus/drug effects , Esters , Foscarnet , Indicators and Reagents , Nucleic Acid Synthesis Inhibitors , Phosphonoacetic Acid/analogs & derivatives , Phosphonoacetic Acid/pharmacology , Simplexvirus/enzymology , Structure-Activity Relationship , Viral Plaque AssayABSTRACT
Analogues of pyrophosphate have been tested as inhibitors of influenza virus-RNA polymerase activity in cell-free assays. The most active compound, phosphonoformic acid (PFA), reduced the polymerase activity to 50 per cent at a concentration of 20 muM. The inhibition was dependent on the type of divalent cation present in the assay. PFA at a concentration of 400 muM also inhibited the influenza virus plaque formation by 90 per cent.
Subject(s)
DNA-Directed RNA Polymerases/antagonists & inhibitors , Diphosphates/pharmacology , Orthomyxoviridae/drug effects , Magnesium/pharmacology , Manganese/pharmacology , Orthomyxoviridae/enzymology , Orthomyxoviridae/growth & development , Structure-Activity Relationship , Viral Plaque AssayABSTRACT
Trisodium phosphonoformate selectively inhibits cell-free DNA polymerase activity induced by herpesvirus. The new inhibitor has an antiviral effect on herpes simplex virus types 1 and 2, pseudorables virus, and infectious bovine rhinotracheitis virus in cell culture. It has a good therapeutic activity against cutaneous herpes simplex virus infection in guinea pigs.
Subject(s)
Antiviral Agents , DNA-Directed RNA Polymerases/antagonists & inhibitors , Nucleic Acid Synthesis Inhibitors , Organophosphorus Compounds/pharmacology , Animals , Antiviral Agents/therapeutic use , Antiviral Agents/toxicity , Cell Line , Formates/pharmacology , Formates/toxicity , Guinea Pigs , Herpesviridae Infections/drug therapy , Organophosphorus Compounds/toxicity , Phosphonoacetic Acid/pharmacology , Simplexvirus/enzymologyABSTRACT
Ribavirin 5'-triphosphate (RTP), derived from the broad-spectrum antiviral compound ribavirin (Virazole), can selectively inhibit influenza virus ribonucleic acid polymerase in a cell-free assay. Ribavirin and its 5'-monophosphate have no effect on the polymerase. The inhibition is competitive with respect to adenosine 5'-triphosphate and guanosine 5'-triphosphate. RTP also inhibits ApG- and GpC-stimulated influenza virus ribonucleic acid polymerase. Since ribavirin is phosphorylated in the cell, the inhibition of influenza multiplication in the cell may also be caused by RTP.
