Dual-Action Multivalent Architectures as Potent Influenza A Virus Inhibitors

Influenza therapeutics with broad-spectrum activity and high efficacy are needed to fight emerging viruses, constantly mutating strains, and impending pandemics. An efficient strategy to inhibit influenza replication is to target both its surface proteins i.e. hemagglutinin (HA) and neuraminidase (NA), thereby inhibiting infection by preventing viral adhesion and release from the cell surface. In this study, we discuss the successful design and development of potent inhibitors of influenza A viruses prepared by the multivalent covalent attachment of sialic acid (SA)/sialyllactose (SL) and the commercial drug zanamivir (ZA) to various polymeric or nanoparticle surfaces. We demonstrate that by the optimum multivalent presentation of targeting ligands on a suitable backbone, viral infection is significantly reduced. These multivalent inhibitors achieve more than 99% inhibition. These findings both rationalize the efficient anti-influenza efficacy of multivalent inhibitors and demonstrate that attaching both HA and NA inhibitors to the same backbone confers a synergic mechanism of antiviral action potentially useful for inhibiting the virus even post-infection.