In vitro antiviral activity of some uridine derivatives of 2-deoxy sugars against classical swine fever virus.
Classical swine fever virus glycoproteins: E2, E(rns) (E0) and E1 are detected on the external part of viral particles and play a major role in the initial stages of viral infection. They form heterodimeric and homodimeric complexes needed to effectively infect host cells. Some glycosylation inhibitors, such as tunicamycin, which act at the early stages of glycan chain processing, can influence, not only glycosylation, but also the stability of E2 and E(rns) glycoproteins, effectively inhibiting the formation of glycoprotein complexes and virus yield. In our study we tested two of newly designed uridine derivatives of 2-deoxy sugars, IW3 and IW7 mimicking part of tunicamycin. We showed that inhibitors effectively arrest viral growth with IC(50) of 9 and 7microg/ml respectively, without significant toxicity for mammalian cells. Moreover, IW3 and IW7 reduced the formation of viral glycoproteins E2 and E(rns) in a dose-dependent manner. These compounds were further studied in order to elucidate the molecular mechanism of the antiviral effect using mammalian SK6 and insect Sf9 cell lines. We found that they inhibit N-glycosylation process of viral proteins at the late stage of glycan modification characteristic for mammalian cells. Due to the observed antiviral effect accompanied by low cytotoxicity, these inhibitors are potential candidates for anti-pestivirus therapy.
Department of Molecular Virology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, Poland. ewelina@biotech.ug.gda.pl
Ewelina
E
Krol
Ilona
I
Wandzik
Wieslaw
W
Szeja
Grzegorz
G
Grynkiewicz
Boguslaw
B
Szewczyk
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006692:Classical Swine Fever Virus / Q000187:drug effects*; D003837:Deoxy Sugars / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D018411:Spodoptera; D013552:Swine; D014529:Uridine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000633:toxicity; D014764:Viral Proteins / Q000378:metabolism
D000998:Antiviral Agents; D003837:Deoxy Sugars; D014764:Viral Proteins; D014529:Uridine