Exploring Rigid and Flexible Core Trivalent Sialosides for Influenza Virus Inhibition

Abstract

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.

On the Stability of the Water-Soluble Chlorophyll-Binding Protein (WSCP) Studied by Molecular Dynamics Simulations

“…Molecular dynamics (MD) simulations have become a valuable tool in the last decades to study the dynamical properties of biological systems. − With the help of these simulations combined with other analysis techniques, it is possible to make statements regarding conformational dynamics, − allostery, protein misfolding, and many other relevant biological features. The investigated systems are quite diverse and range from small − to larger biomolecules ,, or even complexes consisting of multiple biomolecules and/or ligands. − …”

Biomimetic Nanomaterial Strategies for Virus Targeting: Antiviral Therapies and Vaccines

“…[56] This finding agreed well with antiviral testing data on rigid and flexible core trivalent sialosides too. [57] Another important design variable has been considering linear versus branched scaffolds. [58] In one promising example, Kwon et al reported the fabrication of a branched polyamidoamine scaffold that mirrored the inter-spacing distance between HA proteins on influenza virus particles and intranasal administration of this scaffold was able to protect mice from lethal influenza virus infection.…”

“…[ 56 ] This finding agreed well with antiviral testing data on rigid and flexible core trivalent sialosides too. [ 57 ] Another important design variable has been considering linear versus branched scaffolds. [ 58 ] In one promising example, Kwon et al.…”

Polyvalent Transition‐State Analogues of Sialyl Substrates Strongly Inhibit Bacterial Sialidases**

“…These multivalent inhibitors proved particularly effective for lowering the binding ability of human adenovirus or influenza virus strains, by blocking trimeric sialic acid binding proteins at the surface of the viral capsides. [10][11][12][13][14] The viral neuraminidase, a homotetrameric enzyme allowing virions release from cell surfaces after sialic acid cleavages, was also efficiently inhibited by the same approach. Oligo-and poly-mers of the drug zanamivir (ZV), showed impressive in vivo protection of infected mice, higher than the parent ZV.…”

“…Virulence factors interfering with host sialoglycans may also be targeted or inhibited efficiently with synthetic glycoclusters bearing several copies of the sialic acid epitope. These multivalent inhibitors proved particularly effective for lowering the binding ability of human adenovirus or influenza virus strains, by blocking trimeric sialic acid binding proteins at the surface of the viral capsides [10–14] . The viral neuraminidase, a homotetrameric enzyme allowing virions release from cell surfaces after sialic acid cleavages, was also efficiently inhibited by the same approach.…”