In the shadow of SARS-CoV-2, influenza seems to be an innocent virus, although new zoonotic influenza viruses evolved by mutations may lead to severe pandemics. According to WHO, there is an urgent need for better antiviral drugs. Blocking viral hemagglutinin with multivalent N-acetylneuraminic acid derivatives is a promising approach to prevent influenza infection. Moreover, dual inhibition of both hemagglutinin and neuraminidase may result in a more powerful effect. Since both viral glycoproteins can bind to neuraminic acid, we have prepared three series of amphiphilic self-assembling 2-thio-neuraminic acid derivatives constituting aggregates in aqueous medium to take advantage of their multivalent effect. One of the series was prepared by the azide-alkyne click reaction, and the other two by the thio-click reaction to yield neuraminic acid derivatives containing lipophilic tails of different sizes and an enzymatically stable thioglycosidic bond. Two of the three bis-octyl derivatives produced proved to be active against influenza viruses, while all three octyl derivatives bound to hemagglutinin and neuraminidase from H1N1 and H3N2 influenza types.

Central European Institute of Technology Masaryk University 625 00 Brno Czech Republic

Department of Applied Chemistry University of Debrecen H 4032 Debrecen Hungary

Department of Biochemistry Faculty of Science Masaryk University 611 37 Brno Czech Republic

Department of Pharmaceutical Chemistry University of Debrecen H 4032 Debrecen Hungary

Doctoral School of Pharmaceutical Sciences University of Debrecen H 4032 Debrecen Hungary

HUN REN UD Molecular Recognition and Interaction Research Group University of Debrecen H 4032 Debrecen Hungary

National Centre for Biomolecular Research Masaryk University 611 37 Brno Czech Republic

National Laboratory of Virology University of Pécs H 7624 Pécs Hungary

Rega Institute for Medical Research KU Leuven B 3000 Leuven Belgium

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