INHIBITION OF FRIEND MURINE LEUKEMIA-VIRUS ACTIVITY BY GUANOSINE THYMIDINE OLIGONUCLEOTIDES/

Oligonucleotides consisting of only deoxyguanosine and deoxythymidine were stable in culture and were able to significantly inhibit Friend M urine Leukemia Virus (FMLV) production in acute cell culture assay sys tems. The oligonucleotides did not share homology with, or possess any complementary (antisense) sequence motifs to the FMLV genome. The gua nosine/thymidine-containing oligonucleotides (GTOs) which demonstrated anti-FMLV activity in acute infection assays were synthesized with na tural phosphodiester (PD) linkages (backbones). The observed antiviral activities of these oligonucleotides increased significantly when the PD backbone was replaced with a phosphorothioate (PT) backbone. Exper iments designed to investigate a potential antiviral mechanism of acti on demonstrated that oligonucleotides tested were capable of blocking virus adsorption. In addition, GTOs with PD backbones were competitive inhibitors of FMLV reverse transcriptase (RT). When the same experime nts were performed using oligonucleotides with PT backbones, all compo unds tested demonstrated significant competitive inhibition of FMLV RT . The measured inhibitory activity of all compounds tested in culture assays was enhanced by at least a factor of 10 when the PD linkages we re replaced with PT. The enhanced antiviral activity exhibited by the sulfur group on the oligonucleotide backbone, and the lack of any desi gned, sequence-specific interactions, suggest that a large percentage of the reported antiviral activity of oligonucleotides containing a ph osphorothioate backbone is due to factors other than rationally design ed, sequence-specific interactions. The ability of GTOs to inhibit FML V in culture, potentially via a number of different mechanisms, makes this a class of compounds which warrants investigation as therapeutic agents to be used against retroviral infections.