title: Antiviral activities of 2,6-diaminopurine-based acyclic nucleoside phosphonates against herpesviruses: In vitro study results with pseudorabies virus (PrV, SuHV-1).
abstract: 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.
authors: Veterinary Research Institute, Department of Pharmacology and Immunotherapy, Brno, Czech Republic.
authors: Darina
authors: D
authors: Zouharova
authors: Veterinary Research Institute, Department of Pharmacology and Immunotherapy, Brno, Czech Republic.
authors: Ivana
authors: I
authors: Lipenska
authors: Veterinary Research Institute, Department of Pharmacology and Immunotherapy, Brno, Czech Republic.
authors: Martina
authors: M
authors: Fojtikova
authors: Veterinary Research Institute, Department of Pharmacology and Immunotherapy, Brno, Czech Republic.
authors: Pavel
authors: P
authors: Kulich
authors: Veterinary Research Institute, Department of Pharmacology and Immunotherapy, Brno, Czech Republic.
authors: Jiri
authors: J
authors: Neca
authors: Veterinary Research Institute, Department of Pharmacology and Immunotherapy, Brno, Czech Republic.
authors: Michal
authors: M
authors: Slany
authors: Veterinary Research Institute, Department of Pharmacology and Immunotherapy, Brno, Czech Republic.
authors: Kamil
authors: K
authors: Kovarcik
authors: Veterinary Research Institute, Department of Pharmacology and Immunotherapy, Brno, Czech Republic.
authors: Pavlina
authors: P
authors: Turanek-Knotigova
authors: Veterinary Research Institute, Department of Pharmacology and Immunotherapy, Brno, Czech Republic.
authors: Frantisek
authors: F
authors: Hubatka
authors: Veterinary Research Institute, Department of Pharmacology and Immunotherapy, Brno, Czech Republic.
authors: Hana
authors: H
authors: Celechovska
authors: Veterinary Research Institute, Department of Pharmacology and Immunotherapy, Brno, Czech Republic.
authors: Josef
authors: J
authors: Masek
authors: Veterinary Research Institute, Department of Pharmacology and Immunotherapy, Brno, Czech Republic; International Clinical Research Center, St. Annés University Hospital, Brno, Czech Republic.
authors: Stepan
authors: S
authors: Koudelka
authors: Veterinary Research Institute, Department of Pharmacology and Immunotherapy, Brno, Czech Republic.
authors: Lubomir
authors: L
authors: Prochazka
authors: Veterinary Research Institute, Department of Pharmacology and Immunotherapy, Brno, Czech Republic.
authors: Ludek
authors: L
authors: Eyer
authors: Veterinary Research Institute, Department of Pharmacology and Immunotherapy, Brno, Czech Republic.
authors: Jana
authors: J
authors: Plockova
authors: Veterinary Research Institute, Department of Pharmacology and Immunotherapy, Brno, Czech Republic.
authors: Eliska
authors: E
authors: Bartheldyova
authors: King's College London, Institute of Pharmaceutical Science, London, United Kingdom, and GlobalAcorn Ltd., London, United Kingdom.
authors: Andrew D
authors: AD
authors: Miller
authors: Veterinary Research Institute, Department of Pharmacology and Immunotherapy, Brno, Czech Republic; Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, and Faculty of Science, University of South Bohemia, Ceske Budejovice, Czech Republic.
authors: Daniel
authors: D
authors: Ruzek
authors: Veterinary Research Institute, Department of Pharmacology and Immunotherapy, Brno, Czech Republic; Palacky University of Olomouc, Faculty of Medicine, Department of Immunology, Czech Republic.
authors: Milan
authors: M
authors: Raska
authors: Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Prague, Czech Republic.
authors: Zlatko
authors: Z
authors: Janeba
authors: Veterinary Research Institute, Department of Pharmacology and Immunotherapy, Brno, Czech Republic. Electronic address: turanek@vri.cz.
authors: Jaroslav
authors: J
authors: Turanek
mesh_terms: D015075:2-Aminopurine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects; D004285:Dogs; D006564:Herpesviridae / Q000187:drug effects*; D066298:In Vitro Techniques; D061985:Madin Darby Canine Kidney Cells; D046529:Microscopy, Electron, Transmission; D063065:Organophosphonates / Q000737:chemistry / Q000494:pharmacology*; D011557:Pseudorabies / Q000188:drug therapy; D014709:Vero Cells
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D015075:2-Aminopurine; C007300:2,6-diaminopurine
keywords: Acyclic nucleoside phosphonates; Antiviral drugs; Cidofovir; DNA polymerase; DNA viruses; Pseudorabies