Scientists at Triplex Pharmaceutical Corp. have discovered guanine-thymine oligonucleotides (GTOs) that appear to inhibit the functioningof the human immunodeficiency virus.GTOs work though a unique nucleic acid protein interaction thatinhibits the life cycle of HIV, unlike antisense "code-blocker" drugsthat work by canceling genetic messages, as reported in the June issueof the Journal of Acquired Immune Deficiency Syndromes.In in vitro assay experiments, the GTOs inhibited two indicators ofHIV activity: the formation of giant multinucleated cells (syncitia) andthe production of viral antigen p24. And the inhibiting effect on HIVactivity lasted for more than seven days after GTOs were removedfrom the cell culture, the scientists reported.Joseph Zendegui, Triplex's associate director for commercialdevelopment, said The Woodlands, Texas company is moving into thepre-clinical phase of development prior to the filing of aninvestigational new drug application. He said the company is nowfiguring out the mechanism by which the compounds work in order tobetter design them."We have done quite a lot to improve the activity of these compoundsby altering their structure. We've arrived at a specific structure that weintend to promote and to move along in development," Zendegui said.In their study, the scientists noted that oligonucleotide compoundscomposed of only deoxyguanosine and deoxythymidine were able tosignificantly inhibit HIV type-1-induced syncitium formation and virusproduction (as measured by p24 core antigen expression) in an acuteinfection assay system. They said this indicates that GTOs can impairvirus production in culture and not just block the formation of giantmultinucleated cells."The oligonucleotides did not share any homology with or possess anycomplementary (antisense) sequence motifs to the HIV-1 genome," theresearchers noted.While the oligonucleotides with a phosphodiester (PD) backbone wereeffective in inhibiting HIV, the researchers found that the antiviralactivities of these molecules increased when the PD backbone wasreplaced with a phosphorothioate backbone in a dose-dependentmanner.According to the scientists, "these findings suggest that a portion of anoligonucleotide's antiviral activity occurs via mechanisms other thanthe code-blocking `antisense' mechanism and that the addition of asulfur group to the backbone of an oligonucleotide enhances thealternative, as yet undetermined, mechanism(s) of action." n
-- Philippa Maister
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