Influenza is one of the most widespread viral infections worldwide and represents a major public health problem. The risk that one of the next pandemics is caused by an influenza strain is high. It is important to develop broad‐spectrum influenza antivirals to be ready for any possible vaccine shortcomings. Anti‐influenza drugs are available but they are far from ideal. Arguably, an ideal antiviral should target conserved viral domains and be virucidal, that is, irreversibly inhibit viral infectivity. Here, a new class of broad‐spectrum anti‐influenza macromolecules is described that meets these criteria and display exceedingly low toxicity. These compounds are based on a cyclodextrin core modified on its primary face with long hydrophobic linkers terminated either in 6'sialyl‐N‐acetyllactosamine (6’SLN) or in 3’SLN. SLN enables nanomolar inhibition of the viruses while the hydrophobic linkers confer irreversibility to the inhibition. The combination of these two properties allows for efficacy in vitro against several human or avian influenza strains, as well as against a 2009 pandemic influenza strain ex vivo. Importantly, it is shown that, in mice, one of the compounds provides therapeutic efficacy when administered 24 h post‐infection allowing 90% survival as opposed to no survival for the placebo and oseltamivir.

Highlights Entry inhibitors might overcome the limitation of viral mutation. Antiviral research benefits from a broad-spectrum approach. Sialic acids can serve as a platform to create broad-spectrum antiviral drugs. Sialic-acid-targeting drugs such as DAS-181 are promising antiviral strategies. Multivalency is crucial when designing sialic-acid-based receptor analogues.

Dengue virus (DENV) causes 390 million infections per year. Infections can be asymptomatic or range from mild fever to severe haemorrhagic fever and shock syndrome. Currently, no effective antivirals or safe universal vaccine is available. In the present work we tested different gold nanoparticles (Aunp) coated with ligands ω-terminated with sugars bearing multiple sulfonate groups. We aimed to identify compounds with antiviral properties due to irreversible (virucidal) rather than reversible (virustatic) inhibition. The ligands varied in length, in number of sulfonated groups as well as their spatial orientation induced by the sugar head groups. We identified two candidates, a glucose-and a lactose-based ligand showing a low ec 50 (effective concentration that inhibit 50% of the viral activity) for DENV-2 inhibition, moderate toxicity and a virucidal effect in hepatocytes with titre reduction of Median tissue culture infectious Dose log 10 tciD 50 2.5 and 3.1. Molecular docking simulations complemented the experimental findings suggesting a molecular rationale behind the binding between sulfonated head groups and DENV-2 envelope protein. Dengue virus (DENV) belongs to the family Flaviviridae which are usually transmitted by mosquitos or ticks and are responsible for a variety of human diseases mainly haemorrhagic fevers (Dengue, yellow fever, West Nile) but also encephalitis and jaundice and lately Zika 1. According to the WHO 4 serotypes of Dengue exist DENV1-4. The risk of dengue infections is now present in 128 countries affecting almost half of the world population and resulting in 390 million of infections per year 2,3. Infections lead to diseases with large variety of severity ranging from asymptomatic to mild dengue fever and to severe dengue haemorrhagic fever and dengue shock syndrome with about 500,000 people yearly requiring hospitalization 4,5. Currently, there is no effective antiviral or safe universal vaccine for DENV infections. The only available vaccine (DENGVAXIA), recently approved by FDA, presents high risk to unexposed individuals and is therefore administered to people with laboratory-confirmed previous dengue infection 4. The continuous increase of DENV infections in endemic areas as well as the lack of efficient countermeasures underline the need for new therapeutics. There are different routes to interrupt the DENV replication cycle: (i) inhibiting intracellular targets such as two of the main DENV enzymes, namely protease 6-8 and RNA-dependent RNA polymerase 9-18 or (ii) structural glycoprotein envelope (E) protein of the DENV 4,19. Inhibiting the entry step is an attractive approach to prevent viral infections 20. The search for DENV entry inhibitors focused on the main three domains on the E protein, the stem domain, hydrophobic pocket in the hinge domain and the receptor binding domain 19 .

Influenza is one of the most widespread viral infections worldwide and represents a major public health problem. The risk of new pandemics remains high and it is likely that the development of a vaccine against strongly virulent influenza strains would take too long, hence would not help the initial fight of the pandemic. Antiviral drugs are available but they are far from ideal. Arguably, the ideal antiviral should target conserved viral domains and be virucidal, i.e. irreversibly inhibit viral infectivity. Here, we describe a new class of anti-influenza macromolecules that meets these criteria and displays exceedingly low toxicity. These compounds are based on a cyclodextrin core modified on its primary face with long hydrophobic linkers terminated in 6'sialyl-N-acetyllactosamine (6'SLN) or 3'SLN. SLN enables nanomolar inhibition of the viruses while the hydrophobic linkers confer irreversibility to the inhibition. We show that these cyclodextrins are effective against several human or avian influenza strains in vitro, as well as against a 2009 pandemic influenza strain ex vivo and in vivo. Importantly, replacing the hydrophobic linkers with hydrophilic ones results in molecules that are totally ineffective ex vivo, confirming the importance of the virucidal mechanism in the quest of a truly effective antiviral drug.. 1

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