Binding of a N,N'-bisheteryl derivative of dispirotripiperazine to heparan sulfate residues on the cell surface specifically prevents infection of viruses from different families.
N,N'-bisheteryl derivatives of dispirotripiperazine (DSTP) are a novel class of antiviral compounds with some of their representatives very effectively inhibiting the replication of herpes simplex virus type 1 (HSV-1) in cell culture. Using one representative of these compounds, the N,N'-bis(1-oxido[1,2,5]oxadiazolo[3,4-d]pyrimidin-7-yl)-3,12-diaza-6,9-diazonia(5,2,5,2)dispirohexadecane dichloride (DSTP 27), we here further tried to elucidate the molecular mechanisms responsible for the antiviral activity. The results from plaque reduction assays under a variety of conditions suggest that inhibition of HSV-1 strain Kupka replication by DSTP 27 occurs at the level of viral attachment by blockade of heparan sulfate (HS) structures on the cell surface that are used as viral receptors. In contrast to heparin and pentosan polysulfate, pretreatment of cells with DSTP 27 resulted in efficient inhibition of viral adsorption and replication persisting several hours after removal of the inhibitor. Specific binding of DSTP 27 to heparin was demonstrated in vitro. Titrations of gC-positive and gC-negative pseudorabies virus (PrV) mutants on HS-positive and HS-negative cell lines confirmed that inhibitory action of DSTP 27 is strictly HS dependent. Aside from HSV-1 Kupka and PrV, DSTP 27 efficiently inhibits growth of several HSV-1 and HSV-2 strains, among them aciclovir/foscarnet-resistant strains, human cytomegalovirus, human respiratory syncytial virus, and human immunodeficiency viruses known to attach to the cell surface via HS.
Schmidtke
M
M
Institute of Virology and Antiviral Therapy, Friedrich Schiller University of Jena, Winzerlaer Str. 10, D-07745, Jena, Germany. michaela.schmidtke@med.uni-jena.de
Karger
A
A
Meerbach
A
A
Egerer
R
R
Stelzner
A
A
Makarov
V
V
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism*; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000472:pathogenicity; D011558:Herpesvirus 1, Suid / Q000187:drug effects* / Q000235:genetics; D018258:Herpesvirus 2, Human / Q000187:drug effects; D006801:Humans; D009154:Mutation; D010069:Oxadiazoles / Q000378:metabolism / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*; D011991:Receptors, Virus / Q000187:drug effects* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D006497:Heparan Sulfate; D010069:Oxadiazoles; D010879:Piperazines; D011743:Pyrimidines; D011991:Receptors, Virus; C476527:N,N'-bis(1-oxido(1,2,5)oxadiazolo(3,4-d)pyrimidin-7-yl)-3,12-diaza-6,9-diazonia(5,2,5,2)dispirohexadecane dichloride