Sialyl‐LacNAc‐PNA⋅DNA Concatamers by Rolling‐Circle Amplification as Multivalent Inhibitors of Influenza A Virus Particles. (9th January 2019)

• Record Type: Journal Article
• Authors: Bandlow, Victor; Lauster, Daniel; Ludwig, Kai; Hilsch, Malte; Reiter‐Scherer, Valentin; Rabe, Jürgen P.; Böttcher, Christoph; Herrmann, Andreas; Seitz, Oliver
• Is Part Of: Chembiochem. Volume 20:Number 2(2019)
• Page Start: 159
• Page End: 165
• Publication Date: 2019-01-09
• Subjects: antiviral agents -- influenza -- inhibitors -- multivalency -- nucleic acids -- rolling-circle amplification; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201800643
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: The surfaces of influenza A virus (IAV) particles are packed with hundreds of homo‐trimeric hemagglutinins (HAs). Monovalent sugars have low affinity for HA, but distance‐optimized bivalent sialyl‐LacNAc (SLN) conjugates bind it with 10 3 ‐fold enhanced potency. Herein, we describe the oligomerization of distance‐optimized bivalent binders by branched and linear hybridization on long repetitive DNA templates. The most effective complexes fully inhibited IAVs at a DNA template concentration of 10 −9 m . Although a 10 −2 m concentration of free trisaccharide ligand is required for full inhibition of the virus, DNA templating enables a 10 4 ‐fold reduction in the amount of sugar required. Notably, hybridization‐induced rigidification of the DNA templates increased the serospecificity. Cryo‐TEM analysis revealed that both spaghetti‐type linear forms and cotton‐ball‐like clusters are able to bridge several adjacent HA molecules on the IAV surface. Programmed self‐assembly of ligand–nucleic acid conjugates on long DNA templates might provide generic access to target‐specific, high‐affinity binders of proteins on globular objects such as cells and viruses. Abstract : Chain gang : A chain of ligands for enhanced binding of influenza A virus particles has been built by rolling‐circle amplification and subsequent concatenation of sugar–peptide nucleic acid conjugates by linear or branched hybridization on long DNA templates.