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Towards Improved Oligonucleotide Therapeutics Through Faster Target Binding Kinetics
Author(s) -
Menzi Mirjam,
Wild Bettina,
Pradère Ugo,
Malinowska Anna L.,
Brunschweiger Andreas,
Lightfoot Helen L.,
Hall Jonathan
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201701670
Subject(s) - oligonucleotide , linker , surface plasmon resonance , spermine , rna , aptamer , biophysics , chemistry , duplex (building) , kinetics , polyamine , combinatorial chemistry , binding selectivity , biochemistry , dna , biology , nanotechnology , gene , materials science , microbiology and biotechnology , enzyme , physics , quantum mechanics , computer science , nanoparticle , operating system
When used as inhibitors of gene expression in vivo, oligonucleotides require modification of their structures to boost their binding affinity for complementary target RNAs. To date, hundreds of modifications have been designed and tested but few have proven to be useful. Among those investigated are mono‐ and polyamino‐groups. These are positively charged at physiological pH and have been appended to oligonucleotides in an effort to reduce electrostatic repulsion during hybridization to RNAs, but have generally shown relatively minor benefits to binding. We conjugated spermine to uracils in oligonucleotides via a triazole linker so that the polyamine fits in the major groove of a subsequently formed RNA‐duplex. The modifications produced large increases in target‐binding affinity of the oligonucleotides. Using surface plasmon resonance‐based assays, we showed that the increases derived mainly from faster annealing ( k on ). We propose that the spermine fragments play a similar role to that of natural polyamines during oligonucleotide–target interactions in cells, and may be advantageous for oligonucleotides that operate catalytic mechanisms.