[en] Anti-adhesion strategies based on multivalent glycosylated molecules have emerged as promising antiviral tools to block early stages of viral infection. Herein, we report the design, synthesis, and evaluation of a series of porphyrin-based glycoclusters bearing sialic acid (SA) or 9-O-acetyl SA units, connected via linkers of varying length, polarity and rigidity. Their ability to inhibit virus-host cell interaction was assessed against wild-type, Alpha, Delta, JN.1 and KP.3 pseudotyped SARS-CoV-2 variants spanning the virus's evolutionary trajectory. The same inhibition pattern was measured with lived SARS-CoV-2 Delta variant. Although a small erosion of the SA affinity for the spike protein could be observed over the variants, all glycoclusters displayed robust and broad-spectrum neutralizing activity, highlighting the conserved role of SA-mediated recognition. Porphyrins bearing 9Ac-SA always displayed slightly better anti-effective properties than their SA counterparts. The engineering of the linkers distributing the SA ligands to the porphyrin central core proved successful as it could decrease the IC50's up to 4 times. The best optimized tetrameric inhibitors displayed a 60-fold enhanced activity compared to their monomers (15-fold per ligand). This work contributes both to the development and the improvement of antiviral agents and to a better understanding of viral evolution that drives SARS-CoV-2 infection.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Lioret, Vivian; Research Unit of Organic Chemistry, Department of Chemistry, University of Namur, NARILIS (Namur Research Institute of Life Science), Rue de Bruxelles 61, 5000 Namur, Belgium
Gillot, Constant; Research Unit in Clinical Pharmacology and toxicology, Faculty of Medicine, University of Namur, NARILIS (Namur Research Institute of Life Science), Rue de Bruxelles 61, 5000 Namur, Belgium
Hologne, Marie ; Université de Liège - ULiège > Département des maladies infectieuses et parasitaires (DMI) > Vaccinologie vétérinaire
Ha, Jenny; Research Unit of Organic Chemistry, Department of Chemistry, University of Namur, NARILIS (Namur Research Institute of Life Science), Rue de Bruxelles 61, 5000 Namur, Belgium
Strilets, Dmytro; Research Unit of Organic Chemistry, Department of Chemistry, University of Namur, NARILIS (Namur Research Institute of Life Science), Rue de Bruxelles 61, 5000 Namur, Belgium
Lubrano Di Scampamorte, Laurent; Research Unit of Organic Chemistry, Department of Chemistry, University of Namur, NARILIS (Namur Research Institute of Life Science), Rue de Bruxelles 61, 5000 Namur, Belgium
Gillet, Laurent ; Université de Liège - ULiège > Département des maladies infectieuses et parasitaires (DMI) > Vaccinologie vétérinaire
Douxfils, Jonathan; Research Unit in Clinical Pharmacology and toxicology, Faculty of Medicine, University of Namur, NARILIS (Namur Research Institute of Life Science), Rue de Bruxelles 61, 5000 Namur, Belgium
Vincent, Stéphane P; Research Unit of Organic Chemistry, Department of Chemistry, University of Namur, NARILIS (Namur Research Institute of Life Science), Rue de Bruxelles 61, 5000 Namur, Belgium. Electronic address: stephane.vincent@unamur.be
Language :
English
Title :
Sialylated porphyrins optimized as anti-infective agents against SARS-CoV-2 variants.
UNamur - University of Namur F.R.S.-FNRS - Fonds de la Recherche Scientifique
Funding text :
The authors are grateful to Fonds National de la Recherche Scientifique (FNRS, post-doctoral grant to VL (PDR T.0241.23), charg\u00E9 de recherche position to DS) and Actions de Recherche Concert\u00E9e (ARC, PhD grant to JH). The authors acknowledge the use of the UNamur technological platforms MaSUN, PC2, LOS and electron microscopy.
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