Aureonitol, a Fungi-Derived Tetrahydrofuran, Inhibits Influenza Replication by Targeting Its Surface Glycoprotein Hemagglutinin

Abstract

The influenza virus causes acute respiratory infections, leading to high morbidity and mortality in groups of patients at higher risk. Antiviral drugs represent the first line of defense against influenza, both for seasonal infections and pandemic outbreaks. Two main classes of drugs against influenza are in clinical use: M2-channel blockers and neuraminidase inhibitors. Nevertheless, because influenza strains that are resistant to these antivirals have been described, the search for novel compounds with different mechanisms of action is necessary. Here, we investigated the anti-influenza activity of a fungi-derived natural product, aureonitol. This compound inhibited influenza A and B virus replication. This compound was more effective against influenza A(H3N2), with an EC50 of 100 nM. Aureonitol cytoxicity was also very low, with a CC50 value of 1426 μM. Aureonitol inhibited influenza hemagglutination and, consequently, significantly impaired virus adsorption. Molecular modeling studies revealed that aureonitol docked in the sialic acid binding site of hemagglutinin, forming hydrogen bonds with highly conserved residues. Altogether, our results indicate that the chemical structure of aureonitol is promising for future anti-influenza drug design.

Decarboxylative alkenylation

“…Aureonitol ( 95 ) is a tetrahydrofuran-containing natural product discovered in 1979 from Helichrysum aureonitens ( Figure 3F ). 24 A strategic decarboxylative dienylation of 94 delivers 95 in 32% yield with complete selectivity (>20:1 E/Z ) as controlled by the chemistry used to fashion the diene nucleophile. Application of this transformation simplifies the synthesis as 94 can be made in 7 simple steps from inexpensive (+)-xylose.…”

Inhibitory effect of microalgae and cyanobacteria extracts on influenza virus replication and neuraminidase activity

“…Oseltamivir carboxylate (100 − 3.2 µM) (OST-car; kindly donated by Hoffman-La Roche Inc., Basel, Switzerland) was used as a control. For influenza titration, the supernatants were harvested at 48 hpi, and the influenza virus was titrated by TCID50/mL using MDCK cells (5 × 104 cells/well in 96-well plates) through the Reed and Muench method ( Reed & Mounch, 1938 ; Sacramento et al, 2015 ). Non-linear regression of the dose response curves was performed to determine the 50% inhibitory effect on viral replication (EC 50 ) for the extracts and reference compound (OST-car).…”

Small Molecule Inhibitors of Influenza Virus Entry

“…In addition, a natural product derived from the fungus Chaetomium Kuntze ex Fries ( Chaetomiaceae ), aureonitol ( Figure 2 b), also shows effective inhibition against both IAV and IBV [ 38 ]. MOA studies demonstrated that aureonitol inhibits influenza hemagglutination and consequently impairs virus adsorption significantly [ 38 ].…”

“…In addition, a natural product derived from the fungus Chaetomium Kuntze ex Fries ( Chaetomiaceae ), aureonitol ( Figure 2 b), also shows effective inhibition against both IAV and IBV [ 38 ]. MOA studies demonstrated that aureonitol inhibits influenza hemagglutination and consequently impairs virus adsorption significantly [ 38 ]. Molecular modeling studies suggested that aureonitol can fit well to the SA binding site of HA and interact with several highly conserved residues via hydrogen bonds [ 38 ].…”