Systematic chemical modifications of single stranded siRNAs significantly improved CTNNB1 mRNA silencing

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 18; pp. 4513 - 4517
• Main Authors: Chang, Wonsuk, Pei, Yi, Guidry, Erin N., Zewge, Daniel, Parish, Craig A., Sherer, Edward C., DiMuzio, Jillian, Zhang, Hangchun, South, Victoria J., Strapps, Walter R., Sepp-Lorenzino, Laura, Colletti, Steven L., Stanton, Matthew G.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.09.2016
• Subjects: beta Catenin - genetics; Chemical modification; Gene Silencing; HEK293 Cells; Humans; Oligonucleotide; RNA interference; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Single stranded siRNA; Chemical modification; Oligonucleotide; RNA interference; Single stranded siRNA
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.07.064

[Display omitted] Single-stranded silencing RNAs (ss siRNA), while not as potent as duplex RNAs, have the potential to become a novel platform technology in RNA interference based gene silencing by virtue of their simplicity and plausibly favorable characteristics in pharmacokinetics and biodistribution. Like other therapeutic pharmaceutical agents, ss siRNA can be optimized to achieve higher potency through a structure–activity based approach. Systematic chemical modification at each position of a 21-mer oligonucleotide identified 2′,5′-linked 3′-deoxythymidine (3dT) at position 1 and locked nucleic acids (LNAs) at the seed region as key components to afford significant enhancement in knockdown activity both in vitro and in vivo. Further optimization by additional chemical modifications should enable ss siRNA as an alternative gene silencing modality.