Activities of Acyclic Nucleoside Phosphonates against Orf Virus in Human and Ovine Cell Monolayers and Organotypic Ovine Raft Cultures

Pozzo, Fabiana Dal; Andrei, Gracíela; Holý, Antonı́n; Oord, Joost van den; Scagliarini, Alessandra; Clercq, Erik De; Snoeck, Robert

doi:10.1128/aac.49.12.4843-4852.2005

Cited by 37 publications

(33 citation statements)

References 31 publications

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“…The EC 50 s of compounds in the first class of ANPs against CMLV were similar to those observed in the HEL and PHK cell lines against two other, related orthopoxviruses, vaccinia virus (strains Lister, Lederle, and Copenhagen) and cowpox virus (strain Brighton) (29,40). Similarly, the selective and potent activity of HPMPO-DAPy against CMLV is consistent with previous reports on vaccinia virus, cowpox virus, and orf virus in both human and ovine cell monolayers (12,16). The antiviral efficacies of the compounds belonging to the first and second classes of ANPs against CMLV replication were confirmed by virus yield reduction assays, with EC 99 s ranging from 3 M for cHPMPA to 64 M for cHPMPC against CML1 in HEL cells.…”

Section: Discussionsupporting

confidence: 76%

Activities of Several Classes of Acyclic Nucleoside Phosphonates against Camelpox Virus Replication in Different Cell Culture Models

Duraffour

Snoeck

Krečmerová

et al. 2007

Antimicrob Agents Chemother

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Section: Discussionsupporting

confidence: 76%

Activities of Several Classes of Acyclic Nucleoside Phosphonates against Camelpox Virus Replication in Different Cell Culture Models

Duraffour

Snoeck

Krečmerová

et al. 2007

Antimicrob Agents Chemother

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“…1), which is one of the most potent of the ANP-based antipoxvirus agents. We have previously shown that this compound was among the most effective ANPs in the treatment of VACV infections, and it was also highly effective in the inhibition of camelpox virus and Orf virus replication in organotypic epithelial raft cultures (11,23,48). (S)-HPMPDAP has also been proven to be active in different models of VACV infection in mice, and several prodrugs of (S)-HPMPDAP are currently under development (our unpublished data).…”

Section: Times In Medium Containing An Escalating Dose Of (S)-1-[3-hymentioning

confidence: 99%

Mechanism of Antiviral Drug Resistance of Vaccinia Virus: Identification of Residues in the Viral DNA Polymerase Conferring Differential Resistance to Antipoxvirus Drugs

Gammon

Snoeck²,

Fiten

et al. 2008

J Virol

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The acyclic nucleoside phosphonate (ANP) family of drugs shows promise as therapeutics for treating poxvirus infections. However, it has been questioned whether the utility of these compounds could be compromised through the intentional genetic modification of viral sequences by bioterrorists or the selection of drug resistance viruses during the course of antiviral therapy. To address these concerns, vaccinia virus (strain Lederle) was passaged 40 times in medium containing an escalating dose of (S)-1-[3-hydroxy-2-(phosphonomethoxypropyl)-2,6-diaminopurine [(S)-HPMPDAP], which selected for mutant viruses exhibiting a ϳ15-foldincreased resistance to the drug. (S)-HPMPDAP-resistant viruses were generated because this compound was shown to be one of the most highly selective and effective ANPs for the treatment of poxvirus infections. DNA sequence analysis revealed that these viruses encoded mutations in the E9L (DNA polymerase) gene, and marker rescue studies showed that the phenotype was produced by a combination of two (A684V and S851Y) substitution mutations. The effects of these mutations on drug resistance were tested against various ANPs, both separately and collectively, and compared with E9L A314T and A684V mutations previously isolated using selection for resistance to cidofovir, i.e., (S)-1-[3-hydroxy-2-(phosphonomethoxypropyl)cytosine]. These studies demonstrated a complex pattern of resistance, although as a general rule, the double-mutant viruses exhibited greater resistance to the deoxyadenosine than to deoxycytidine nucleotide analogs. The S851Y mutant virus exhibited a low level of resistance to dCMP analogues but high-level resistance to dAMP analogues and to 6-[3-hydroxy-2-(phosphonomethoxy)propoxy]-2,4-diaminopyrimidine, which is considered to mimic the purine ring system. Notably, (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-3-deazaadenine retained marked activity against most of these mutant viruses. In vitro studies showed that the A684V mutation partially suppressed a virus growth defect and mutator phenotype created by the S851Y mutation, but all of the mutant viruses still exhibited a variable degree of reduced virulence in a mouse intranasal challenge model. Infections caused by these drug-resistant viruses in mice were still treatable with higher concentrations of the ANPs. These studies have identified a novel mechanism for the development of mutator DNA polymerases and provide further evidence that antipoxviral therapeutic strategies would not readily be undermined by selection for resistance to ANP drugs.

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“…As shown before, the lesions in the raft cultures infected with VV, which can be seen after histological examination, are similar to the ones seen in the clinic (18). These three-dimensional epithelial culture systems have recently been successfully used to determine the activities of ANP derivatives against VV, orf virus, and herpesviruses (2,8,18). Organotypic cultures were prepared as described previously (2,18).…”

mentioning

confidence: 99%

Activities of Alkoxyalkyl Esters of Cidofovir (CDV), Cyclic CDV, and ( S )-9-(3-Hydroxy-2-Phosphonylmethoxypropyl)Adenine against Orthopoxviruses in Cell Monolayers and in Organotypic Cultures

Lebeau

Andrei

Pozzo

et al. 2006

Antimicrob Agents Chemother

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The potencies of several alkoxyalkyl esters of acyclic nucleoside phosphonates against vaccinia virus and cowpox virus were evaluated in cell monolayers and three-dimensional epithelial raft cultures. Prodrugs were at least 20-fold more active than their parent compounds. Octadecycloxyethyl-(S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine emerged as the most potent derivative.Smallpox has been declared eradicated since 1980 (5). However, due to the potential threat of variola virus as a weapon for bioterrorism (4) and the increasing number of infections with monkeypox virus (11), it is essential that adequate antiviral drugs be developed. Cidofovir (CDV) has already proven to be active against orthopoxviruses (9,10,14,16,18). However, this drug needs to be administered intravenously and is potentially nephrotoxic. Recently, it was shown that alkoxyalkyl and alkyl esters of CDV and cyclic cidofovir (cCDV) were more active against vaccinia virus (VV) and cowpox virus (CPV) in human foreskin fibroblasts than their parent compounds due in part to an increased penetration through the cell membrane (13,15). In vivo studies indicate that the prodrugs are highly orally bioavailable and are as effective as parenterally administered CDV for the treatment of VV-or CPV-infected mice (6,7,17).The activities of various alkoxyalkyl esters of the acyclic nucleoside phosphonate (ANP) analogues CDV [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine; HPMPC; Vistide], e Selectivity index (ratio of CC 50 to EC 50 ).

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Activities of Acyclic Nucleoside Phosphonates against Orf Virus in Human and Ovine Cell Monolayers and Organotypic Ovine Raft Cultures

Cited by 37 publications

References 31 publications

Activities of Several Classes of Acyclic Nucleoside Phosphonates against Camelpox Virus Replication in Different Cell Culture Models

Activities of Several Classes of Acyclic Nucleoside Phosphonates against Camelpox Virus Replication in Different Cell Culture Models

Mechanism of Antiviral Drug Resistance of Vaccinia Virus: Identification of Residues in the Viral DNA Polymerase Conferring Differential Resistance to Antipoxvirus Drugs

Activities of Alkoxyalkyl Esters of Cidofovir (CDV), Cyclic CDV, and ( S )-9-(3-Hydroxy-2-Phosphonylmethoxypropyl)Adenine against Orthopoxviruses in Cell Monolayers and in Organotypic Cultures

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