دورية أكاديمية
Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators
| العنوان: | Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators |
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| المؤلفون: | Flierl, Ulrike, Nero, Tracy L., Lim, Bock, Arthur, JF, Yao, Yu, Jung, Stephanie M., Gitz, E., Pollitt, Alice Y., Zaldivia, Maria T.K, Jandrot-Perrus, Martine, Gardiner, Elizabeth |
| المصدر: | Journal of Experimental Medicine |
| بيانات النشر: | Rockefeller University Press |
| المجموعة: | Australian National University: ANU Digital Collections |
| مصطلحات موضوعية: | Keywords: 4 amino 7 tert butyl 5 (4 chlorophenyl)pyrazolo[3,4 d]pyrimidine, antisense oligonucleotide, C reactive protein, collagen, Fc receptor IIa, glycoprotein VI, integrin, nucleotide, oligodeoxynucleotide phosphorothioate, oligonucleotide, reactive oxygen meta |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | unknown |
| تدمد: | 0022-1007 |
| العلاقة: | http://hdl.handle.net/1885/152319Test; https://openresearch-repository.anu.edu.au/bitstream/1885/152319/5/01_Flierl_Phosphorothioate_backbone_2015.pdf.jpgTest |
| DOI: | 10.1084/jem.20140391 |
| الإتاحة: | https://doi.org/10.1084/jem.20140391Test http://hdl.handle.net/1885/152319Test https://openresearch-repository.anu.edu.au/bitstream/1885/152319/5/01_Flierl_Phosphorothioate_backbone_2015.pdf.jpgTest |
| رقم الانضمام: | edsbas.6313537B |
| قاعدة البيانات: | BASE |
| تدمد: | 00221007 |
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| DOI: | 10.1084/jem.20140391 |