Mucin‐Inspired, High Molecular Weight Virus Binding Inhibitors Show Biphasic Binding Behavior to Influenza A Viruses

Abstract

Multivalent binding inhibitors are a promising new class of antivirals that prevent virus infections by inhibiting virus binding to cell membranes. The design of these inhibitors is challenging as many properties, for example, inhibitor size and functionalization with virus attachment factors, strongly influence the inhibition efficiency. Here, virus binding inhibitors are synthesized, the size and functionalization of which are inspired by mucins, which are naturally occurring glycosylated proteins with high molecular weight (MDa range) and interact efficiently with various viruses. Hyperbranched polyglycerols (hPGs) with molecular weights ranging between 10 and 2600 kDa are synthesized, thereby hitting the size of mucins and allowing for determining the impact of inhibitor size on the inhibition efficiency. The hPGs are functionalized with sialic acids and sulfates, as suggested from the structure of mucins, and their inhibition efficiency is determined by probing the inhibition of influenza A virus (IAV) binding to membranes using various methods. The largest, mucin‐sized inhibitor shows potent inhibition at pm concentrations, while the inhibition efficiency decreases with decreasing the molecular weight. Interestingly, the concentration‐dependent IAV inhibition shows a biphasic behavior, which is attributed to differences in the binding affinity of the inhibitors to the two IAV envelope proteins, neuraminidase, and hemagglutinin.

Polysulfates Block SARS‐CoV‐2 Uptake through Electrostatic Interactions**

“…Our group has developed several synthetic polyglycerol sulfates (LPGS and HPGS) as heparin‐mimetic polymers in the past years [32, 33] . With similar charge density, the polyglycerol sulfates exhibit lower anticoagulant activity than heparin [32] .…”

A Dynamic, Supramolecular View on the Multivalent Interaction between Influenza Virus and Host Cell

“…[127] When a virus and a multivalent inhibitor form a dynamic complex, the decoy receptors are in competition with cellular receptors and cleavable receptors may be cleaved by NA. [128] To ensure irreversible inhibition, antivirals may be used that combine multivalent binding with inhibition of NA [129] or a virucidal activity. [130,131] The multivalency of IAV may play similar roles in its interaction with the immune system.…”

Polysulfate hemmen durch elektrostatische Wechselwirkungen die SARS‐CoV‐2‐Infektion**

“…In den vergangen Jahren haben wir mehrere synthetische Polyglycerolsulfate (LPGS und HPGS) als Heparin‐Mimetika entwickelt [32, 33] . Bei ähnlicher Ladungsdichte zeigen die Polyglycerolsulfate eine geringere gerinnungshemmende Aktivität als Heparin [32] .…”

“…In den vergangen Jahren haben wir mehrere synthetische Polyglycerolsulfate (LPGS und HPGS) als Heparin-Mimetika entwickelt. [32,33] Bei ähnlicher Ladungsdichte zeigen die Polyglycerolsulfate eine geringere gerinnungshemmende Aktivitäta ls Heparin. [32] Die Hemmaktivitätd ieser Polysulfate gegenüber SARS-CoV-2 wurde eingehend untersucht und mit der von Heparin verglichen, um einen Ansatzpunkt fürd as Design zukünftiger Inhibitoren zu erhalten.…”