ABSTRACT
We have previously shown that alpha-2-O-methyl-5-N-thioacetylneuraminic acid (alpha-Neu5thioAc2Me) has a higher affinity to bromelain-treated hemagglutinin (HA) of influenza A virus than sialic acid from natural sources (Machytka et al., 1993, FEBS Lett. 334, 117-120). We have now compared the inhibitory effects of alpha-Neu5thioAc2Me and other sialic acid analogs on receptor binding and plaque formation of intact influenza A viruses. When alpha-Neu5thioAc2Me was polymerized by conjugation to polyacrylamide, its affinity to HA increased 10(3)-fold. When analyzed by plaque reduction, the alpha-Neu5thioAc2 polymer was about 10 times more efficient as an inhibitor of virus replication than the alpha-Neu5Ac2 polymer, stressing the importance of sulfur at C5. The S-glycoside alpha-2-S-methyl-5-N-thioacetylneuraminic acid (alpha-Neu5thioAc2SMe) had the same affinity to HA as alpha-Neu5thioAc2Me, but was resistant to neuraminidase. The alpha-Neu5thioAc2S polymer interfered with the replication of a wider spectrum of influenza A virus subtypes than the alpha-Neu5thioAc2 polymer. The results indicate that the alpha-Neu5thioAc2S polymer has the potential to be used as an inhibitor of influenza virus infection.
Subject(s)
Antiviral Agents/pharmacology , Hemagglutinins, Viral/metabolism , Influenza A virus/drug effects , Neuraminic Acids/pharmacology , Polymers/pharmacology , Acrylic Resins , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Binding, Competitive , Chickens , Glycosides/metabolism , Hemagglutinin Glycoproteins, Influenza Virus , Humans , Influenza A virus/metabolism , Influenza A virus/physiology , Neuraminic Acids/chemical synthesis , Neuraminic Acids/chemistry , Neuraminic Acids/metabolism , Neuraminidase/metabolism , Polymers/chemical synthesis , Polymers/chemistry , Polymers/metabolism , Receptors, Virus/metabolism , Viral Plaque Assay , Virus Replication/drug effects , alpha-Fetoproteins/metabolismABSTRACT
The binding of influenza A virus hemagglutinin to its cell surface receptor, alpha-linked 5-N-acetylneuraminic acid (sialic acid), was studied in solution. The effect of structural modifications introduced into the N-acetyl group of the sialic acid on the binding was monitored by determining the dissociation constants by proton nuclear magnetic resonance (1H NMR) spectroscopy. Methyl alpha-glycoside of N-thioacetylneuraminic acid showed high, whereas the corresponding N-methylcarbamoylneuraminic acid exhibited relatively low binding affinity towards the hemagglutinin.
