Antiviral effects of phosphonoformate (pfa, foscarnet sodium)

Öberg, Bo

doi:10.1016/0163-7258(89)90097-1

Cited by 174 publications

(42 citation statements)

References 167 publications

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“…Although the inhibition of viral DNA polymerases by PFA has been described many years ago (14,26,27), the detailed mechanism of action of this compound remains elusive (1,28). Previous biochemical studies about the mechanism of action of PFA focused on the inhibition of DNA polymerization.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, it has been consistently found that PFA competitively inhibited the ATP-PP i exchange reaction (26,29), and PFA has been used as a pyrophosphate analog for product inhibition studies in a variety of DNA polymerases (29,30). The interaction between foscarnet and pyrophosphate is not completely straightforward, however, because high levels of resistance to foscarnet are usually not associated with high levels of resistance to PP i (14,26,28).…”

Section: Discussionmentioning

confidence: 99%

“…RT (14). Despite its activity toward HIV-1, PFA is used exclusively to treat opportunistic viral infections such as human cytomegalovirus, acyclovir-resistant herpes simplex, and varicella-zoster virus infections in patients with immunodeficiency.…”

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confidence: 99%

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Selective Excision of Chain-terminating Nucleotides by HIV-1 Reverse Transcriptase with Phosphonoformate as Substrate

Cruchaga

Ansó

Rouzaut

et al. 2006

Journal of Biological Chemistry

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A major mechanism for human immunodeficiency virus 1 (HIV-1) reverse transcriptase (RT) resistance to nucleoside analogs involves the phosphorolytical removal of the chain-terminating nucleotide from the 3-end of the primer. In this work, we analyzed the effect of phosphonoformate (PFA) and other pyrophosphate (PP i ) analogs on PP i -and ATP-dependent phosphorolysis catalyzed by HIV-1 RT. Our experimental data demonstrated that PFA did not behave as a linear inhibitor but as an alternative substrate, allowing RT to remove AZT from a terminated primer through a PFA-dependent mechanism. Interestingly, in non-terminated primers, PFA was not a substrate for this reaction and competitively inhibited PP i -and ATP-dependent phosphorolysis. In fact, binding of PFA to the RT⅐template/primer complex was hindered by the presence of a chain terminator at the 3-end of the primer. Other pyrophosphate analogs, such as phosphonoacetate, were substrates for the excision reaction with both terminated and nonterminated primers, whereas pamidronate, a bisphosphonate that prevents bone resorption, was not a substrate for these reactions and competitively inhibited the phosphorolytic activity of RT. As expected from their mechanisms of action, pamidronate (but not PFA) synergistically inhibits HIV-1 RT in combination with AZTtriphosphate in the presence of PP i or ATP. These results provide new clues about the mechanism of action of PFA and demonstrate that only certain pyrophosphate analogs can enhance the effect of nucleosidic inhibitors by blocking the excision of chain-terminating nucleotides catalyzed by HIV-1 RT. The relevance of these findings in combined chemotherapy is discussed.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Selective Excision of Chain-terminating Nucleotides by HIV-1 Reverse Transcriptase with Phosphonoformate as Substrate

Cruchaga

Ansó

Rouzaut

et al. 2006

Journal of Biological Chemistry

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“…The pyrophosphate analog foscarnet (phosphonoformic acid, PFA) is the third approved anti-HCMV drug that inhibits UL54 ( Fig. 1) (28,29). However, toxicity, problems with oral bioavailability, and the rapid development of resistance can limit the clinical utility of each of the approved drugs.…”

mentioning

confidence: 99%

“…PFA is a broad spectrum antiviral agent that was shown to inhibit various polymerases, including enzymes encoded by herpes simplex virus (HSV), human herpesvirus, HCMV, and the reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1) (28,29). Progress has been made in elucidating the mechanism of inhibition of HIV-1 RT (30,31).…”

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confidence: 99%

Engineering of a Chimeric RB69 DNA Polymerase Sensitive to Drugs Targeting the Cytomegalovirus Enzyme

Tchesnokov

Obikhod

Schinazi

et al. 2009

Journal of Biological Chemistry

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Detailed structural and biochemical studies with the human cytomegalovirus (HCMV UL54) DNA polymerase are hampered by difficulties to obtain this enzyme in large quantities. The crystal structure of the related RB69 DNA polymerase (gp43) is often used as a model system to explain mechanisms of inhibition of DNA synthesis and drug resistance. However, here we demonstrate that gp43 is ϳ400-fold less sensitive to the pyrophosphate analog foscarnet, when compared with UL54. The RB69 enzyme is also able to discriminate against the nucleotide analog inhibitor acyclovir. In contrast, the HCMV polymerase is able to incorporate this compound with similar efficiency as observed with its natural counterpart. In an attempt to identify major determinants for drug activity, we replaced critical regions of the nucleotide-binding site of gp43 with equivalent regions of the HCMV enzyme. We show that chimeric gp43-UL54 enzymes that contain residues of helix N and helix P of UL54 are resensitized against foscarnet and acyclovir. Changing a region of three amino acids of helix N showed the strongest effects, and changes of two segments of three amino acids in helix P further contributed to the reversal of the phenotype. The engineered chimeric enzyme can be produced in large quantities and may therefore be a valuable surrogate system in drug development efforts. This system may likewise be used for detailed structural and biochemical studies on mechanisms associated with drug action and resistance.Infection with the human cytomegalovirus (HCMV), 2 which belongs to the Herpesviridae, remains an important health problem in immunocompromised persons (1-7). Several drugs that target the viral DNA polymerase (UL54) have been developed to treat the infection (8 -12). Cidofovir (CDV), ganciclovir (GCV), or its prodrug valganciclovir are nucleotide or nucleoside analog inhibitors, respectively, that are intracellularly phosphorylated to their triphosphate form and compete with natural nucleotide pools for incorporation (13)(14)(15)(16)(17)(18)(19)(20). These compounds are characterized by an acyclic sugar moiety with the equivalent of a 3Ј-hydroxyl group that is required for the next nucleotide incorporation event (21). Thus, once incorporated, these compounds interfere with DNA synthesis at various positions downstream (18,22,23). In contrast, compounds that lack the 3Ј-hydroxyl group, such as the antiherpetic drug acyclovir (ACV) (Fig. 1), act as chain terminators (24,25). Although active against HCMV, ACV is not approved for treatment of HCMV infection, and its efficacy is inferior to GCV or CDV (8,26,27). The pyrophosphate analog foscarnet (phosphonoformic acid, PFA) is the third approved anti-HCMV drug that inhibits UL54 (Fig. 1) (28, 29). However, toxicity, problems with oral bioavailability, and the rapid development of resistance can limit the clinical utility of each of the approved drugs.PFA is a broad spectrum antiviral agent that was shown to inhibit various polymerases, including enzymes encoded by herpes simplex virus (HSV), ...

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Antiviral Agents

Revankar¹,

Robins²

2000

Kirk-Othmer Encyclopedia of Chemical Technology

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Viral infections are among the greatest causes of human morbidity, and it is estimated that in developed countries more than 60% of all the episodes of human illness result from viral infections. High virus infection rates also occur among pets, livestock, and plants. The high morbidity and the resulting economic loss caused by these infections have generated tremendous efforts in recent years to develop antiviral agents. Since viruses propagate only within living cells, the development of antiviral drugs which would disrupt the viral replication without affecting the metabolism of the host cell was initially believed to be difficult, if not impossible. However, dramatic progress in viral molecular biology has now made it possible to identify enzymatic processes which are unique to virus‐infected cells. As a consequence, it is becoming feasible to design chemical compounds which identify infected cells, block a specific step in viral replication, and leave uninfected cells unharmed. The majority of antiviral drugs which are under clinical development today generally interrupt viral nucleic acid synthesis. These compounds possess considerable selectivity against virus‐induced enzymes. This article discusses agents exhibiting significant antiviral activity against viral infections in animal model systems. One of the simplest molecules found to inhibit the replication of DNA viruses in animals is phosphonoformic acid (PFA), CH 3 O 5 P. PFA has undergone clinical evaluation in humans for the treatment of recurrent genital herpes, hepatitis B viral infection, and acquired immunodeficiency syndrome (AIDS), as well as cytomegalovirus (CMV) infection of bone marrow and renal transplant patients. Levamisole (6‐phenyl‐2,3,5,6‐tetrahydroimidazol[2,1‐ b ]thiazole), C 11 H 12 N 2 S, was found to be effective against herpes virus infections in humans. Several pyrimidine bases have been found to inhibit herpes virus‐induced keratitis in rabbits, eg, 2‐amino‐4,6‐dichloropyrimidine, C 4 H 3 Cl 2 N 3 , and 1‐allyl‐6‐chloro‐3,5‐diethyluracil, C 11 H 15 ClN 2 O 2 . The most successful clinical antiviral agents belong to the nucleoside category. Nucleoside analogues with potent antiviral activity have been known since idoxuridine and trifluridine were shown to be efficacious against herpes keratitis more than 30 years ago. However, the therapeutic usefulness of these early nucleosides was limited because of mutagenic, teratogenic, carcinogenic, cytostatic, or cytotoxic side effects. Recently the specificity of antiviral action of this class of compounds has been significantly improved; potent and highly selective nucleoside antiviral agents have now been developed. These include cytosine derivatives, purine nucleoside derivatives, adenine derivatives, and acyclic purine nucleosides. Among agents active against RNA viruses, 1,2‐bis(5‐methoxy‐2‐benzimidazol‐2‐yl)‐1,2‐ethanediol, C 18 H 18 N 4 O 4 , was found to be active against an experimentally induced rhino virus infection in chimpanzees. However, the in vivo antiviral efficacy was accompanied by significant toxicity. Amantadine hydrochloride (1‐adamantanamine hydrochloride), \documentclass{article}\usepackage{amssymb}\pagestyle{empty}\begin{document}${{\rm{C}}{\rm{H}}{\rm{N}}{\rm{{\cdot{}}}}{\rm{HCl}}1710}$\end{document} , is a narrow‐spectrum agent active only against influenza A virus. It became the first antiviral drug available for systemic use in the United States when it was approved by the FDA in 1966 for use against Asian influenza. A structurally related drug, rimantadine hydrochloride, (α‐methyl‐1‐adamantanemethylamine hydrochloride), \documentclass{article}\usepackage{amssymb}\pagestyle{empty}\begin{document}${{\rm{C}}{\rm{H}}{\rm{N}}{\rm{{\cdot{}}}}{\rm{HCl}}2112}$\end{document} , is widely used in Russia to treat influenza A virus. Lipophilic β‐diketones have exhibited significant in vivo activity against a number of RNA viruses, and adenosine and guanosine analogues have been found to be active against both RNA and DNA viruses. One of the broad‐spectrum antiviral agents that emerged from ICN Pharmaceuticals is an azole ribonucleoside, 1‐β‐ D ‐ribofuranosyl‐1,2,4‐triazole‐3‐carboxamide, designated as ribavirin, C 8 H 12 N 4 O 5 . Ribavirin has been studied in more animals and against more viruses than any other antiviral agent known today. It is active in cell culture against approximately 85% of all viruses studied. Viral strains susceptible to ribavirin have not been found to develop a resistance to the drug. The resistance against ribavirin is less likely because the drug exhibits multiple sites of antiviral action. Retroviruses as a class are often found to be responsible for persistent viral infections. Retroviruses are unique RNA viruses characterized by the transcription of their single‐stranded RNA into the double‐stranded DNA of the host cell using the viral enzyme reverse transcriptase. AIDS is an example of such a persistent and latent human viral infection. Following the identification of a retrovirus, HIV, as the etiological agent of AIDS, an intense effort has been made to identify drugs for the treatment or prevention of this debilitating, lethal disease. Several 2′,3′‐dideoxyribonucleosides of purine and pyrimidine were discovered to be potent inhibitors of HIV replication in vitro . Considerable data has also accumulated on in vitro antiHIV testing of acyclic and carbocyclic nucleoside analogues. 3′‐Azido‐3′‐deoxythymidine (retrovir, zidovudine, AZT), C 10 H 13 N 5 O 4 , 2,′3′‐dideoxycytidine (DDC), C 9 H 13 N 3 O 3 , and 2′,3′‐dideoxyinosine (DDI), C 10 H 12 N 4 O 3 , have become widely available for the treatment of AIDS and approved by the FDA for treatment of advanced AIDS cases.

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Antiviral effects of phosphonoformate (pfa, foscarnet sodium)

Cited by 174 publications

References 167 publications

Selective Excision of Chain-terminating Nucleotides by HIV-1 Reverse Transcriptase with Phosphonoformate as Substrate

Selective Excision of Chain-terminating Nucleotides by HIV-1 Reverse Transcriptase with Phosphonoformate as Substrate

Engineering of a Chimeric RB69 DNA Polymerase Sensitive to Drugs Targeting the Cytomegalovirus Enzyme

Antiviral Agents

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