title: Synergistic effect of phosphorothioate, 5'-vinylphosphonate and GalNAc modifications for enhancing activity of synthetic siRNA.
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.
authors.affiliation: Ionis Pharmaceuticals Inc., 2855 Gazelle Ct., Carlsbad, CA 92010, United States. Electronic address: tprakash@isisph.com.
authors.forename: Thazha P
authors.initials: TP
authors.lastname: Prakash
authors.affiliation: Ionis Pharmaceuticals Inc., 2855 Gazelle Ct., Carlsbad, CA 92010, United States.
authors.forename: Garth A
authors.initials: GA
authors.lastname: Kinberger
authors.affiliation: Ionis Pharmaceuticals Inc., 2855 Gazelle Ct., Carlsbad, CA 92010, United States.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Murray
authors.affiliation: Ionis Pharmaceuticals Inc., 2855 Gazelle Ct., Carlsbad, CA 92010, United States.
authors.forename: Alfred
authors.initials: A
authors.lastname: Chappell
authors.affiliation: Ionis Pharmaceuticals Inc., 2855 Gazelle Ct., Carlsbad, CA 92010, United States.
authors.forename: Stan
authors.initials: S
authors.lastname: Riney
authors.affiliation: Ionis Pharmaceuticals Inc., 2855 Gazelle Ct., Carlsbad, CA 92010, United States.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.affiliation: Ionis Pharmaceuticals Inc., 2855 Gazelle Ct., Carlsbad, CA 92010, United States.
authors.forename: Walt F
authors.initials: WF
authors.lastname: Lima
authors.affiliation: Ionis Pharmaceuticals Inc., 2855 Gazelle Ct., Carlsbad, CA 92010, United States.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Swayze
authors.affiliation: Ionis Pharmaceuticals Inc., 2855 Gazelle Ct., Carlsbad, CA 92010, United States.
authors.forename: Punit P
authors.initials: PP
authors.lastname: Seth
mesh_terms: D000116:Acetylgalactosamine / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010710:Phosphates / Q000737:chemistry / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014753:Vinyl Compounds / Q000737:chemistry / Q000378:metabolism*
chemical_list: D063065:Organophosphonates; D010710:Phosphates; D034741:RNA, Small Interfering; D014753:Vinyl Compounds; C433467:vinylphosphonic acid; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D000116:Acetylgalactosamine; C035638:thiophosphoric acid
keywords: 3′-GalNAc cluster; 5′-Vinylphosphonate siRNA; Alternating F/OMe siRNA; Fully modified siRNA; siRNA phosphorothioates