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Synergistic effect of phosphorothioate, 5'-vinylphosphonate and GalNAc modifications for enhancing activity of synthetic siRNA.
Prakash, Thazha P; Kinberger, Garth A; Murray, Heather M; Chappell, Alfred; Riney, Stan; Graham, Mark J; Lima, Walt F; Swayze, Eric E; Seth, Punit P.
Afiliación
  • Prakash TP; Ionis Pharmaceuticals Inc., 2855 Gazelle Ct., Carlsbad, CA 92010, United States. Electronic address: tprakash@isisph.com.
  • Kinberger GA; Ionis Pharmaceuticals Inc., 2855 Gazelle Ct., Carlsbad, CA 92010, United States.
  • Murray HM; Ionis Pharmaceuticals Inc., 2855 Gazelle Ct., Carlsbad, CA 92010, United States.
  • Chappell A; Ionis Pharmaceuticals Inc., 2855 Gazelle Ct., Carlsbad, CA 92010, United States.
  • Riney S; Ionis Pharmaceuticals Inc., 2855 Gazelle Ct., Carlsbad, CA 92010, United States.
  • Graham MJ; Ionis Pharmaceuticals Inc., 2855 Gazelle Ct., Carlsbad, CA 92010, United States.
  • Lima WF; Ionis Pharmaceuticals Inc., 2855 Gazelle Ct., Carlsbad, CA 92010, United States.
  • Swayze EE; Ionis Pharmaceuticals Inc., 2855 Gazelle Ct., Carlsbad, CA 92010, United States.
  • Seth PP; Ionis Pharmaceuticals Inc., 2855 Gazelle Ct., Carlsbad, CA 92010, United States.
Bioorg Med Chem Lett ; 26(12): 2817-2820, 2016 06 15.
Article en En | MEDLINE | ID: mdl-27161280
ABSTRACT
Chemical modifications are essential to improve metabolic stability and pharmacokinetic properties of siRNA to enable their systemic delivery. We investigated the effect of combing the phosphorothioate (PS) modification with metabolically stable phosphate analog (E)-5'-vinylphosphonate and GalNAc cluster conjugation on the activity of fully 2'-modified siRNA in cell culture and mice. Our data suggest that integrating multiple chemical approaches in one siRNA molecule improved potency 5-10 fold and provide a roadmap for developing more efficient siRNA drugs.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfatos / Acetilgalactosamina / Compuestos de Vinilo / ARN Interferente Pequeño / Fosfohidrolasa PTEN / Organofosfonatos Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2016 Tipo del documento: Article
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfatos / Acetilgalactosamina / Compuestos de Vinilo / ARN Interferente Pequeño / Fosfohidrolasa PTEN / Organofosfonatos Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2016 Tipo del documento: Article