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Sialyl‐LacNAc‐PNA⋅DNA Concatamers by Rolling‐Circle Amplification as Multivalent Inhibitors of Influenza A Virus Particles
Author(s) -
Bandlow Victor,
Lauster Daniel,
Ludwig Kai,
Hilsch Malte,
ReiterScherer Valentin,
Rabe Jürgen P.,
Böttcher Christoph,
Herrmann Andreas,
Seitz Oliver
Publication year - 2019
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201800643
Subject(s) - dna , bivalent (engine) , chemistry , rolling circle replication , nucleic acid , template , virus , influenza a virus , click chemistry , conjugate , nucleic acid thermodynamics , biochemistry , biophysics , microbiology and biotechnology , combinatorial chemistry , polymerase , biology , virology , nanotechnology , materials science , mathematical analysis , mathematics , organic chemistry , base sequence , metal
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.