Antiviral activities of 2,6-diaminopurine-based acyclic nucleoside phosphonates against herpesviruses: In vitro study results with pseudorabies virus (PrV, SuHV-1)
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
26854349
DOI
10.1016/j.vetmic.2016.01.010
PII: S0378-1135(16)30010-4
Knihovny.cz E-resources
- Keywords
- Acyclic nucleoside phosphonates, Antiviral drugs, Cidofovir, DNA polymerase, DNA viruses, Pseudorabies,
- MeSH
- 2-Aminopurine analogs & derivatives chemistry pharmacology MeSH
- Antiviral Agents chemistry pharmacology MeSH
- Cell Line MeSH
- Madin Darby Canine Kidney Cells MeSH
- Herpesviridae drug effects MeSH
- Organophosphonates chemistry pharmacology MeSH
- Pseudorabies drug therapy MeSH
- Dogs MeSH
- DNA Replication drug effects MeSH
- In Vitro Techniques MeSH
- Microscopy, Electron, Transmission MeSH
- Vero Cells MeSH
- Animals MeSH
- Check Tag
- Dogs MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 2-Aminopurine MeSH
- 2,6-diaminopurine MeSH Browser
- Antiviral Agents MeSH
- Organophosphonates MeSH
Pseudorabies virus (PrV), a causative agent of Aujeszky's disease, is deadly to most mammals with the exception of higher primates and men. This disease causes serious economic loses among farm animals, especially pigs, yet many European countries are today claimed to be Aujeszky's disease free because of the discovery of an efficient vaccination for pigs. In reality, the virus is still present in wild boar. Current vaccines are neither suitable for dogs nor are there anti-PrV drugs approved for veterinary use. Therefore, the disease still represents a high threat, particularly for expensive hunting dogs that can come into close contact with infected boars. Here we report on the anti-PrV activities of a series of synthetic diaminopurine-based acyclic nucleoside phosphonate (DAP-ANP) analogues. Initially, all synthetic DAP-ANPs under investigation are shown to exhibit minimal cytotoxicity by MTT and XTT tests (1-100μM range). Thereafter in vitro infection models are established using PrV virus SuHV-1, optimized on PK-15 and RK-13 cell lines. Out of the six DAP-ANP analogues tested, analogue VI functionalized with a cyclopropyl group on the 6-amino position of the purine ring proves the most effective antiviral DAP-ANP analogue against PrV infection, aided by sufficient hydrophobic character to enhance bioavailability to its cellular target viral DNA-polymerase. Four other DAP-ANP analogues with functional groups introduced to the C2'position are shown ineffective against PrV infection, even with favourable hydrophobic properties. Cidofovir(®), a drug approved against various herpesvirus infections, is found to exert only low activity against PrV in these same in vitro models.
Institute of Organic Chemistry and Biochemistry The Czech Academy of Sciences Prague Czech Republic
Veterinary Research Institute Department of Pharmacology and Immunotherapy Brno Czech Republic
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