Abstract
Current treatment options for influenza virus infections in humans are limited and therefore the development of novel antivirals is of high priority. Inhibiting influenza virus attachment to host cells would provide an early and efficient block of the infection and thus, receptor analogs have been considered as options for antiviral treatment. Here, we describe the rapid and efficient synthesis of PAMAM dendrimers conjugated with either 3′-sialyllactose (3SL) or 6′-sialyllactose (6SL) and their potential to inhibit a diverse range of human and avian influenza virus strains. We show in a hemagglutination inhibition (HAI) assay that human IAV strains can be inhibited by (6SL)- and to a lesser extent also by (3SL)-conjugated PAMAM dendrimers. In contrast, avian strains could only be inhibited by (3SL)-conjugated dendrimers. Importantly, the differential sensitivities of human and avian IAV to the two types of sialyllactose-conjugated dendrimers could be confirmed in cell-based neutralization assays. Based on our findings, we suggest to further develop both, (3SL)- and (6SL)-conjugated PAMAM dendrimers, as influenza virus inhibitors.
Highlights
Influenza A virus (IAV) is the causative agent of influenza, a respiratory febrile disease in humans that is of medical and economic importance[1]
We show that hemagglutination of human IAV strains can be inhibited by (6SL)- and (3SL)-conjugated PAMAM dendrimers, whereas avian strains were only sensitive to (3SL)-PAMAMs
The trisaccharides 3SL and 6SL were first derivatized at their reducing end to cyclic carbamate[24], which enabled the efficient conjugation of the sialyllactoses to primary amines in PAMAM backbones (Fig. 1)
Summary
Influenza A virus (IAV) is the causative agent of influenza, a respiratory febrile disease in humans that is of medical and economic importance[1]. Conjugation of SA to polymers has been explored and proven more promising as higher affinity binding and improved stability can be achieved[17,18,19,20,21,22] Dendritic polymers, such as polyamidoamine (PAMAM) dendrimers, can be conjugated to diverse ligands and represent one option to display SA in a multivalent manner[23]. Kwon and colleagues developed this approach further by coupling 6′-sialyllactose (6SL), a representative of the human-type IAV receptor, to PAMAM dendrimers rather than coupling SA directly to dendrimers[21] This strategy revealed that valency, and spacing between ligands affects the inhibitory potential. We synthesized PAMAM dendrimers branched with either 3SL or 6SL using a rapid and efficient method and assessed their potential to inhibit a diverse range of human and avian influenza virus strains. We conclude that both, (3SL)- and (6SL)-conjugated PAMAM dendrimers, should be further developed as IAV inhibitors
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