Exploring Rigid and Flexible Core Trivalent Sialosides for Influenza Virus Inhibition

Herein, the chemical synthesis and binding analysis of functionalizable rigid and flexible core trivalent sialosides bearing oligoethylene glycol (OEG) spacers interacting with spike proteins of influenza A virus (IAV) X31 is described. Although the flexible Tris‐based trivalent sialosides achieved micromolar binding constants, a trivalent binder based on a rigid adamantane core dominated flexible tripodal compounds with micromolar binding and hemagglutination inhibition constants. Simulation studies indicated increased conformational penalties for long OEG spacers. Using a systematic approach with molecular modeling and simulations as well as biophysical analysis, these findings emphasize on the importance of the scaffold rigidity and the challenges associated with the spacer length optimization. The rigid adamantane‐based trivalent sialoside with optimized oligoethylene glycol spacer was found to be the most potent candidate against IAV/X31, showing an inhibitory constant in the micromolar range. It binds to hemagglutinin of the influenza virus and thus inhibits the virus–cell attachment.