Synergistic effect of phosphorothioate, 5′-vinylphosphonate and GalNAc modifications for enhancing activity of synthetic siRNA. Issue 12 (15th June 2016)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 12(2016)
• Page Start: 2817
• Page End: 2820
• Publication Date: 2016-06-15
• Subjects: 3′-GalNAc cluster -- 5′-Vinylphosphonate siRNA -- Fully modified siRNA -- Alternating F/OMe siRNA -- siRNA phosphorothioates; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.04.063
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.