Sialylated porphyrins optimized as anti-infective agents against SARS-CoV-2 variants

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.