Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators

Flierl, U., Nero, T. L., Lim, B., Arthur, J. F., Yao, Y., Jung, S. M., Gitz, E., Pollitt, A. Y. ORCID: https://orcid.org/0000-0001-8706-5154, Zaldivia, M. T. K., Jandrot-Perrus, M., Schäfer, A., Nieswandt, B., Andrews, R. K., Parker, M. W., Gardiner, E. E. and Peter, K. (2015) Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators. The Journal of Experimental Medicine, 212 (2). pp. 129-137. ISSN 1540-9538 doi: 10.1084/jem.20140391

Abstract/Summary

Nucleotide-based drug candidates such as antisense oligonucleotides, aptamers, immunoreceptor-activating nucleotides, or (anti)microRNAs hold great therapeutic promise for many human diseases. Phosphorothioate (PS) backbone modification of nucleotide-based drugs is common practice to protect these promising drug candidates from rapid degradation by plasma and intracellular nucleases. Effects of the changes in physicochemical properties associated with PS modification on platelets have not been elucidated so far. Here we report the unexpected binding of PS-modified oligonucleotides to platelets eliciting strong platelet activation, signaling, reactive oxygen species generation, adhesion, spreading, aggregation, and thrombus formation in vitro and in vivo. Mechanistically, the platelet-specific receptor glycoprotein VI (GPVI) mediates these platelet-activating effects. Notably, platelets from GPVI function-deficient patients do not exhibit binding of PS-modified oligonucleotides, and platelet activation is fully abolished. Our data demonstrate a novel, unexpected, PS backbone-dependent, platelet-activating effect of nucleotide-based drug candidates mediated by GPVI. This unforeseen effect should be considered in the ongoing development programs for the broad range of upcoming and promising DNA/RNA therapeutics.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/44789
Item Type	Article
Refereed	Yes
Divisions	Life Sciences > School of Biological Sciences > Biomedical Sciences
Publisher	Rockefeller University Press
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