ABSTRACT
Natural sialic acid-modified compounds are capable of targeting influenza virus hemagglutinin (HA). However, these compounds have limited inhibitory effect because natural O-glycoside bond in these compounds are prone to be cleaved by neuraminidase (NA) on the surface of viruses. In this study, we synthesized NA-resistant sialoside that included unnatural S-glycoside bonds and modified this sialoside on a three-way junction (3WJ) DNA to display complementary distribution to its binding sites on a HA trimer. This S-glycoside-containing sialoside-modified 3WJ DNA showed certain NA resistance and maintained high binding affinity. Importantly, our observations showed that substituting natural O-glycoside with unnatural S-glycoside did not affect the binding affinity of the sialoside-modified 3WJ DNA for viruses. Thus, this study is an important step forward in the development of NA-resistant sialoside derivatives for more effective detection and inhibition of infection by a broad spectrum of viruses.
Subject(s)
DNA/chemistry , Glycosides/chemical synthesis , Hemagglutinin Glycoproteins, Influenza Virus/chemistry , Neuraminidase/chemistry , Sialic Acids/chemistry , Base Sequence , Binding Sites , Nucleic Acid Conformation , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Protein Multimerization , Protein Stability , Proteolysis , SolutionsABSTRACT
Sialyllactose (SL)-modified trimer DNAs with a similar SL presentation as their binding sites on influenza virus hemagglutinin (HA) trimer were designed and synthesized. These trimer DNAs showed high affinity for various influenza viruses, including A/Puerto Rico/08/34 (H1N1), A/Beijing/262/95 (H1N1), A/Yokohama/77/2008 (H1N1), and A/Panama/2007/99 (H3N2). Thus, presentation of SL residues on three vertexes of the scaffold as well as sialic acid binding sites on the HA trimer regardless of a tri-branched or triangular scaffold are important for high affinity for influenza viruses. These compounds have the potential for use in detection and as inhibitors of a broad spectrum of influenza viruses.
Subject(s)
Antiviral Agents/pharmacology , DNA/pharmacology , Influenza A virus/drug effects , Lactose/analogs & derivatives , Sialic Acids/chemistry , Virus Attachment/drug effects , DNA/chemistry , Humans , Influenza A virus/metabolism , Lactose/chemistryABSTRACT
Epigallocatechin-3-O-gallate (EGCG) is the major catechin component of green tea (Cameria sinensis), and is known to possess antiviral activities against a wide range of DNA viruses and RNA viruses. However, few studies have examined chemical modifications of EGCG in terms of enhanced antiviral efficacy. This paper discusses which steps of virus infection EGCG interferes with, citing previous reports. EGCG appears most likely to inhibits the early stage of infections, such as attachment, entry, and membrane fusion, by interfering with viral membrane proteins. According to the relationships between structure and antiviral activity of catechin derivatives, the 3-galloyl and 5'-OH group of catechin derivatives appear critical to antiviral activities. Enhancing the binding affinity of EGCG to virus particles would thus be important to increase virucidal activity. We propose a newly developed EGCG-fatty acid derivative in which the fatty acid on the phenolic hydroxyl group would be expected to increase viral and cellular membrane permeability. EGCG-fatty acid monoesters showed improved antiviral activities against different types of viruses, probably due to their increased affinity for virus and cellular membranes. Our study promotes the application of EGCG-fatty acid derivatives for the prevention and treatment of viral infections.
Subject(s)
Antiviral Agents/therapeutic use , Catechin/analogs & derivatives , Fatty Acids/therapeutic use , Virus Diseases/drug therapy , Virus Physiological Phenomena , Animals , Antiviral Agents/chemistry , Catechin/chemistry , Catechin/therapeutic use , Fatty Acids/chemistry , Humans , Virus Diseases/metabolism , Virus Diseases/pathologyABSTRACT
Sialic acid present on the cell surface is recognized by hemagglutinin (HA) on the influenza virus in the first step of infection. Therefore, a compound that can efficiently interfere with the interaction between sialic acid and HA might inhibit infection and allow detection of the influenza virus. We focused on the spatial arrangement of sialic acid binding sites on HA and developed 2,3-sialyllactose (2,3-SL)-modified three-way junction (3WJ) DNA molecules with a topology similar to that of sialic acid binding sites. 3WJ DNA with three 2,3-SL residues on each DNA strand showed (8.0 × 104)-fold higher binding affinity for influenza virus A/Puerto Rico/08/34 (H1N1) compared to the 2,3-SL. This result indicated that the glycocluster effect due to clustering on one DNA arm and optimal spatial arrangement of the 3WJ DNA improved the weak interactions between a sialic acid and its binding site on HA. This 3WJ DNA compound has possible application as an inhibitor of influenza infection and for virus sensing.
