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

Duraffour, Sophie; Snoeck, Robert; Krečmerová, Marcela; Oord, Joost van den; Vos, Rita De; Holý, Antonı́n; Crance, Jean‐Marc; Garín, Daniel; Clercq, Erik De; Andrei, Gracíela

doi:10.1128/aac.00838-07

Cited by 49 publications

(24 citation statements)

References 42 publications

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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in different models of VACV infection in mice, and several prodrugs of (S)-HPMPDAP are currently under development (our unpublished data).…”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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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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“…Several of these derivatives have been evaluated in vitro and ex vivo against poxviruses including VACV, CPXV, CMLV, and orf virus replication (16,17,28,42,46,61). As shown in Fig.…”

mentioning

confidence: 99%

Mutations Conferring Resistance to Viral DNA Polymerase Inhibitors in Camelpox Virus Give Different Drug-Susceptibility Profiles in Vaccinia Virus

Duraffour

Andrei

Topalis

et al. 2012

J Virol

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“…204 In recent years, the activity of cidofovir has been further documented against rabbitpox virus in rabbits, 205 mousepox in mice, 206 monkeypox in mice, 207 cowpox in mice 208 [the zoonotic cowpox virus is considered an emerging health threat 209 ] and Cantagalo virus in vitro 210 [Cantagalo virus has been isolated during an outbreak of a pustular disease in dairy farms in Brazil; it may derive from the Brazilian smallpox vaccine 211 ]. Cidofovir has also proven strongly inhibitory to parapoxviruses in vitro, 212 including the orf virus 213,214 and the sea lion poxvirus.…”

Section: D8 Therapeutic Potential Of Cidofovir and Anps For Veterinamentioning

confidence: 99%

Yet another ten stories on antiviral drug discovery (part D): Paradigms, paradoxes, and paraductions

Clercq

2009

Medicinal Research Reviews

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This review article presents the fourth part (part D) in the series of stories on antiviral drug discovery. The stories told in part D focus on: (i) the cyclotriazadisulfonamide compounds; (ii) the {5-[(4-bromophenylmethyl]-2-phenyl-5H-imidazo[4,5-c]pyridine} compounds; (iii) (1H,3H-thiazolo[3,4-a]benzimidazole) derivatives; (iv) T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) and (v) its structurally closely related analogue pyrazine 2-carboxamide (pyrazinamide); (vi) new strategies for the treatment of hemorrhagic fever virus infections, including, as the most imminent, (vii) dengue fever, (viii) the veterinary use of acyclic nucleoside phosphonates; (ix) the potential (off-label) use of cidofovir in the treatment of papillomatosis, particularly RRP (recurrent respiratory papillomatosis); and (x) finally, the prophylactic use of tenofovir to prevent HIV infections.

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

Cited by 49 publications

References 42 publications

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

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

Mutations Conferring Resistance to Viral DNA Polymerase Inhibitors in Camelpox Virus Give Different Drug-Susceptibility Profiles in Vaccinia Virus

Yet another ten stories on antiviral drug discovery (part D): Paradigms, paradoxes, and paraductions

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