Potent sialic acid inhibitors that target influenza A virus hemagglutinin

Abstract

Eradicating influenza A virus (IAV) is difficult, due to its genetic drift and reassortment ability. As the infectious cycle is initiated by the influenza glycoprotein, hemagglutinin (HA), which mediates the binding of virions to terminal sialic acids moieties, HA is a tempting target of anti-influenza inhibitors. However, the complexity of the HA structure has prevented delineation of the structural characterization of the HA protein–ligand complex. Our computational strategy efficiently analyzed > 200,000 records of compounds held in the United States National Cancer Institute (NCI) database and identified potential HA inhibitors, by modeling the sialic acid (SA) receptor binding site (RBS) for the HA structure. Our modeling revealed that compound NSC85561 showed significant antiviral activity against the IAV H1N1 strain with EC50 values ranging from 2.31 to 2.53 µM and negligible cytotoxicity (CC50 > 700 µM). Using the NSC85561 compound as the template to generate 12 derivatives, robust bioassay results revealed the strongest antiviral efficacies with NSC47715 and NSC7223. Virtual screening clearly identified three SA receptor binding site inhibitors that were successfully validated in experimental data. Thus, our computational strategy has identified SA receptor binding site inhibitors against HA that show IAV-associated antiviral activity.

Proteomic and genetic analyses of influenza A viruses identify pan-viral host targets

“…Recent antiviral strategies instead target human sialic acid to block HA binding and IAV entry. For example, sialic acid inhibitors were recently shown to target HA and have antiviral efficacy 96 . Antiviral compound Fludase (DAS181), a bacteria-derived sialidase fusion protein that cleaves sialic acid from epithelium cell surface to prevent IAV entry 97 , enrolled its first patient in a Phase III clinical trial in 2019 and is moving towards FDA approval and clinical use.…”

Molecular Modeling of Viral Type I Fusion Proteins: Inhibitors of Influenza Virus Hemagglutinin and the Spike Protein of Coronavirus

“…In other words, it can prevent HA binding to sialic acid receptors and force additional structural restrictions on the fusogenic transitions of the protein. In [34], molecular modeling techniques in conjunction with biological experiments were used to search for potential HA1 inhibitors. Based on the results of a theoretical assessment of the affinity of more than 200 compounds to the sialic acid binding site, the authors chose the lead To develop a potential RBS inhibitor, it would undoubtedly be efficient to use the crystal structure of HA in a complex with a native ligand.…”

Heparan Sulfate and Sialic Acid in Viral Attachment: Two Sides of the Same Coin?

“…Computational methods have contributed to optimizing the search for HA blockers, allowing for selection among thousands of compounds theoretically and the evaluation of the best candidates experimentally. Some molecules chosen by this methodology are the N-benzyl-4,4,-disubstituted piperidines [ 74 ] and the derivatives of compound NSC8556 [ 75 ]; both showed in vitro effectiveness to inhibit virus entry. So far, the only drugs used against influenza are neuraminidase inhibitors such as oseltamivir.…”