Abstract
This study describes the development of aptamers as a therapy against influenza virus infection. Aptamers are oligonucleotides (like ssDNA or RNA) that are capable of binding to a variety of molecular targets with high affinity and specificity. We have studied the ssDNA aptamer BV02, which was designed to inhibit influenza infection by targeting the hemagglutinin viral protein, a protein that facilitates the first stage of the virus’ infection. While testing other aptamers and during lead optimization, we realized that the dominant characteristics that determine the aptamer’s binding to the influenza virus may not necessarily be sequence-specific, as with other known aptamers, but rather depend on general 2D structural motifs. We adopted QSAR (quantitative structure activity relationship) tool and developed computational algorithm that correlate six calculated structural and physicochemical properties to the aptamers’ binding affinity to the virus. The QSAR study provided us with a predictive tool of the binding potential of an aptamer to the influenza virus. The correlation between the calculated and actual binding was R2 = 0.702 for the training set, and R2 = 0.66 for the independent test set. Moreover, in the test set the model’s sensitivity was 89%, and the specificity was 87%, in selecting aptamers with enhanced viral binding. The most important properties that positively correlated with the aptamer’s binding were the aptamer length, 2D-loops and repeating sequences of C nucleotides. Based on the structure-activity study, we have managed to produce aptamers having viral affinity that was more than 20 times higher than that of the original BV02 aptamer. Further testing of influenza infection in cell culture and animal models yielded aptamers with 10 to 15 times greater anti-viral activity than the BV02 aptamer. Our insights concerning the mechanism of action and the structural and physicochemical properties that govern the interaction with the influenza virus are discussed.
Highlights
In the drug development race against new influenza strains and emerging resistance to current drugs, there is a need for new drugs that act via new mechanisms of action on currently unexploited viral targets [1,2,3,4,5,6]
BioVent has developed a treatment for influenza infection, using the aptamer BV02
In the present study we investigated the anti-influenza DNA aptamer BV02 and compared it to random sequence aptamers with similar length and other physical properties as controls
Summary
In the drug development race against new influenza strains and emerging resistance to current drugs, there is a need for new drugs that act via new mechanisms of action on currently unexploited viral targets [1,2,3,4,5,6] Such a novel target is the hemagglutinin viral protein that facilitates the first stage of the influenza virus infection – the binding to a species-specific host cells in the respiratory epithelium. Binding by blocking the viral hemagglutinin with synthetic DNA aptamers They showed that aptamers that were selected against a specific peptide fragment of hemagglutinin were capable of inhibiting the hemagglutinin binding capacity of the virus, as well as preventing viral infection in tissue culture. In this work we used BV02 aptamer (named A22 in Jeon et al.) as the benchmark and starting point for the lead optimization process and the structure–activity study described in this publication
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