Your browser doesn't support javascript.
loading
Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators.
Flierl, Ulrike; Nero, Tracy L; Lim, Bock; Arthur, Jane F; Yao, Yu; Jung, Stephanie M; Gitz, Eelo; Pollitt, Alice Y; Zaldivia, Maria T K; Jandrot-Perrus, Martine; Schäfer, Andreas; Nieswandt, Bernhard; Andrews, Robert K; Parker, Michael W; Gardiner, Elizabeth E; Peter, Karlheinz.
Afiliação
  • Flierl U; Baker IDI Heart and Diabetes Institute, St. Vincent's Institute of Medical Research, and Bio21 Institute, University of Melbourne, Melbourne, Victoria 3010, Australia Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany.
  • Nero TL; Baker IDI Heart and Diabetes Institute, St. Vincent's Institute of Medical Research, and Bio21 Institute, University of Melbourne, Melbourne, Victoria 3010, Australia Baker IDI Heart and Diabetes Institute, St. Vincent's Institute of Medical Research, and Bio21 Institute, University of Melbourne, Me
  • Lim B; Baker IDI Heart and Diabetes Institute, St. Vincent's Institute of Medical Research, and Bio21 Institute, University of Melbourne, Melbourne, Victoria 3010, Australia.
  • Arthur JF; Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.
  • Yao Y; Baker IDI Heart and Diabetes Institute, St. Vincent's Institute of Medical Research, and Bio21 Institute, University of Melbourne, Melbourne, Victoria 3010, Australia.
  • Jung SM; Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, England, UK.
  • Gitz E; Centre for Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT, England, UK.
  • Pollitt AY; Centre for Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT, England, UK.
  • Zaldivia MT; Baker IDI Heart and Diabetes Institute, St. Vincent's Institute of Medical Research, and Bio21 Institute, University of Melbourne, Melbourne, Victoria 3010, Australia.
  • Jandrot-Perrus M; Institut National de la Santé et de la Recherche Médicale, U1148, 75877 Paris, France.
  • Schäfer A; Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany.
  • Nieswandt B; Rudolf Virchow Centre for Experimental Biomedicine, D-97080 Würzburg, Germany.
  • Andrews RK; Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.
  • Parker MW; Baker IDI Heart and Diabetes Institute, St. Vincent's Institute of Medical Research, and Bio21 Institute, University of Melbourne, Melbourne, Victoria 3010, Australia Baker IDI Heart and Diabetes Institute, St. Vincent's Institute of Medical Research, and Bio21 Institute, University of Melbourne, Me
  • Gardiner EE; Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.
  • Peter K; Baker IDI Heart and Diabetes Institute, St. Vincent's Institute of Medical Research, and Bio21 Institute, University of Melbourne, Melbourne, Victoria 3010, Australia karlheinz.peter@bakeridi.edu.au.
J Exp Med ; 212(2): 129-37, 2015 Feb 09.
Article em En | MEDLINE | ID: mdl-25646267
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Plaquetas / Ativação Plaquetária / Oligonucleotídeos Fosforotioatos Limite: Animals / Humans / Male Idioma: En Revista: J Exp Med Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Plaquetas / Ativação Plaquetária / Oligonucleotídeos Fosforotioatos Limite: Animals / Humans / Male Idioma: En Revista: J Exp Med Ano de publicação: 2015 Tipo de documento: Article