Abstract
Neuraminidase (NA) of influenza viruses enables the virus to access the cell membrane. It degrades the sialic acid contained in extracellular mucin. Later, it is responsible for releasing newly formed virions from the membrane of infected cells. Both processes become key functions within the viral cycle. Therefore, it is a therapeutic target for research of the new antiviral agents. Structure–activity relationships studies have revealed which are the important functional groups for the receptor–ligand interaction. Influenza virus type A NA activity was inhibited by five scaffolds without structural resemblance to sialic acid. Intending small organic compound repositioning along with drug repurposing, this study combined in silico simulations of ligand docking into the known binding site of NA, along with in vitro bioassays. The five proposed scaffolds are N-acetylphenylalanylmethionine, propanoic 3-[(2,5-dimethylphenyl) carbamoyl]-2-(piperazin-1-yl) acid, 3-(propylaminosulfonyl)-4-chlorobenzoic acid, ascorbic acid (vitamin C), and 4-(dipropylsulfamoyl) benzoic acid (probenecid). Their half maximal inhibitory concentration (IC50) was determined through fluorometry. An acidic reagent 2′-O-(4-methylumbelliferyl)-α-dN-acetylneuraminic acid (MUNANA) was used as substrate for viruses of human influenza H1N1 or avian influenza H5N2. Inhibition was observed in millimolar ranges in a concentration-dependent manner. The IC50 values of the five proposed scaffolds ranged from 6.4 to 73 mM. The values reflect a significant affinity difference with respect to the reference drug zanamivir (p < 0.001). Two compounds (N-acetyl dipeptide and 4-substituted benzoic acid) clearly showed competitive mechanisms, whereas ascorbic acid reflected non-competitive kinetics. The five small organic molecules constitute five different scaffolds with moderate NA affinities. They are proposed as lead compounds for developing new NA inhibitors which are not analogous to sialic acid.
Highlights
Influenza is a severe and infectious respiratory disease with high mortality and morbidity rates.Two subtypes of influenza A viruses (H1N1 and H3N2) along with two lineages of influenza B virusesMolecules 2020, 25, 4248; doi:10.3390/molecules25184248 www.mdpi.com/journal/molecules (Victoria and Yamagata) are cocirculating in the human population
Both influenza viruses A and B possess two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA) [3,4]. Both glycoproteins have complementary roles within the viral cycle, despite the fact that both recognize the same molecule in infected host cells, namely the terminal sialic acid monomers on oligomeric glycoconjugates [5,6]
Commercial drugs against this infectious disease in oral dosage forms have been derived from the aforementioned terminal sialic acid which constitutes the natural substrate of NA [7,8]
Summary
Influenza is a severe and infectious respiratory disease with high mortality and morbidity rates.Two subtypes of influenza A viruses (H1N1 and H3N2) along with two lineages of influenza B virusesMolecules 2020, 25, 4248; doi:10.3390/molecules25184248 www.mdpi.com/journal/molecules (Victoria and Yamagata) are cocirculating in the human population. The World Health Organization (WHO) estimates that there are approximately 290,000 to 600,000 annual deaths worldwide associated with the infection [1,2] Both influenza viruses A and B possess two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA) [3,4]. NA mediates a pivotal step in the life cycle of influenza A viruses and thereby contributes to their transmissibility and pathogenicity—all of which characterizes it as a potential viral protein target. Commercial drugs against this infectious disease in oral dosage forms have been derived from the aforementioned terminal sialic acid which constitutes the natural substrate of NA [7,8]
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