Cidofovir and (S)-9-[3-Hydroxy-(2-Phosphonomethoxy)Propyl]Adenine Are Highly Effective Inhibitors of Vaccinia Virus DNA Polymerase When Incorporated into the Template Strand

  title={Cidofovir and (S)-9-[3-Hydroxy-(2-Phosphonomethoxy)Propyl]Adenine Are Highly Effective Inhibitors of Vaccinia Virus DNA Polymerase When Incorporated into the Template Strand},
  author={Wendy C. Magee and Kathy A. Aldern and Karl Y. Hostetler and David H. Evans},
  journal={Antimicrobial Agents and Chemotherapy},
  pages={586 - 597}
ABSTRACT The acyclic nucleoside phosphonate drug (S)-9-[3-hydroxy-(2-phosphonomethoxy)propyl]adenine [(S)-HPMPA], is a broad-spectrum antiviral and antiparasitic agent. Previous work has shown that the active intracellular metabolite of this compound, (S)-HPMPA diphosphate [(S)-HPMPApp], is an analog of dATP and targets DNA polymerases. However, the mechanism by which (S)-HPMPA inhibits DNA polymerases remains elusive. Using vaccinia virus as a model system, we have previously shown that… 

Inhibition of HIV-1 by Octadecyloxyethyl Esters of (S)-[3-Hydroxy-2-(Phosphonomethoxy)Propyl] Nucleosides and Evaluation of Their Mechanism of Action

The synthesized ODE esters of a series of (S)-[3-hydroxy-2-(phosphonomethoxy)propyl] (HPMP) nucleosides suggest that this class of drugs has a broader spectrum of activity than previously shown.

The Octadecyloxyethyl Ester of (S)-9-[3-Hydroxy-2-(Phosphonomethoxy) Propyl]Adenine Is a Potent and Selective Inhibitor of Hepatitis C Virus Replication in Genotype 1A, 1B, and 2A Replicons

HDP and ODE esters of (S)-HPMPA and (R)-H PMPA were evaluated for their activity in hepatitis C virus replicon assays using luciferase ( 1B and 2A replicons) or RNA (1B) quantification.

Alkoxyalkyl Esters of 9-(S)-(3-Hydroxy-2-Phosphonomethoxypropyl) Adenine Are Potent and Selective Inhibitors of Hepatitis B Virus (HBV) Replication In Vitro and in HBV Transgenic Mice In Vivo

The increased antiviral activity appeared to be due in part to the increased uptake and conversion of HDP-(S)-HPMPA to HPMPA diphosphate observed in HepG2 cells in vitro.

The Acyclic 2,4-Diaminopyrimidine Nucleoside Phosphonate Acts as a Purine Mimetic in HIV-1 Reverse Transcriptase DNA Polymerization*

Molecular modeling demonstrates that PMEO-DAPym-pp fits into the active site of HIV-1 RT without significant perturbation of key amino acid residues and mimics an open incomplete purine ring that allows the canonical Watson-Crick base pairing to be maintained.

Inhibition of Herpesvirus Replication by Hexadecyloxypropyl Esters of Purine- and Pyrimidine-Based Phosphonomethoxyethyl Nucleoside Phosphonates

It is indicated that HDP-esterified acyclic nucleoside phosphonates with antiviral activity against HIV also inhibit the replication of some herpesviruses and can extend the spectrum of activity for these compounds.



Intracellular phosphorylation of broad-spectrum anti-DNA virus agent (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine and inhibition of viral DNA synthesis.

The selectivity of (S)-HPMPA as an antiviral agent cannot be attributed to a differential phosphorylation by virus-infected or uninfected cells but resides in a specific inhibitory effect on viral DNA synthesis.

Alkoxyalkyl Esters of (S)-9-[3-Hydroxy-2-(Phosphonomethoxy)Propyl]Adenine Are Potent Inhibitors of the Replication of Wild-Type and Drug-Resistant Human Immunodeficiency Virus Type 1 In Vitro

HP-(S)-HPMPA is also active against herpes simplex virus type 1, human cytomegalovirus, hepatitis B virus, adenoviruses, and orthopoxviruses and is worthy of further evaluation as a possibly therapy for HIV infection.

Synthesis and antiviral evaluation of alkoxyalkyl derivatives of 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)adenine against cytomegalovirus and orthopoxviruses.

The alkoxyalkyl esters of (S)-HPMPA are promising new compounds worthy of further investigation for treatment of infections caused by herpes viruses and orthopoxviruses.

Evaluation of Nucleoside Phosphonates and Their Analogs and Prodrugs for Inhibition of Orthopoxvirus Replication

A number of analogs and potential oral prodrugs of these ANP derivatives have activity against vaccinia virus and cowpox virus in vitro and should be evaluated for their efficacies in animal models.

Mechanism of inhibition of adenovirus DNA replication by the acyclic nucleoside triphosphate analogue (S)-HPMPApp: influence of the adenovirus DNA binding protein.

Inhibition was strongly enhanced in the presence of the adenovirus DNA binding protein (DBP), interpreted to mean that the increased processivity of the polymerization reaction in the absence of DBP leads to increased drug sensitivity.

The Substrate Activity of (S)-9-[3-Hydroxy-(2-phosphonomethoxy)Propyl]Adenine Diphosphate toward DNA Polymerases α, δ and ε

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HDP-CDV seems to circumvent poor cellular uptake by rapid association with cellular membrane phospholipids, whereas CDV uptake proceeds via the slow process of fluid endocytosis, and levels of cidofovir diphosphate (CDV-DP), the active antiviral compound, were >100 times greater with HDP- CDV than levels observed with CDV.

The substrate activity of (S)-9-[3-hydroxy-(2-phosphonomethoxy)propyl]adenine diphosphate toward DNA polymerases alpha, delta and epsilon.

Observations indicate that interaction of HPMPApp with pol alpha, delta and epsilon may contribute to its cellular toxicity and explain its antiviral activity against polyomavirus.

Inhibition of the in vitro growth of Plasmodium falciparum by acyclic nucleoside phosphonates.