Epigenetic Modification 6-Methyladenosine Can Impact the Potency and Specificity of siRNA

Anna M Rydzik; Dirk Gottschling; Eric Simon; Wioletta Skronska-Wasek; Jörg F Rippmann; Doris Riether

doi:10.1002/cbic.202000551

Epigenetic Modification 6-Methyladenosine Can Impact the Potency and Specificity of siRNA

Chembiochem. 2021 Feb 2;22(3):491-495. doi: 10.1002/cbic.202000551. Epub 2020 Oct 23.

Authors

Anna M Rydzik^{1

2}, Dirk Gottschling¹, Eric Simon¹, Wioletta Skronska-Wasek¹, Jörg F Rippmann¹, Doris Riether¹

Affiliations

¹ Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany.
² Current address: Research and Early Development, Respiratory & Immunology, AstraZeneca, 431 83, Mölndal, Sweden.

PMID: 32936508
DOI: 10.1002/cbic.202000551

Abstract

The introduction of N6-methyladenosine (m6 A) into siRNA targeting Factor VII impacts its potency in cells and has a significant influence on the selectivity of siRNA, including reduced off-targeting. These effects are dependent on the position of m6 A in the siRNA duplex, with some of the sequences identified as more potent and/or selective than their non-methylated counterpart. These findings broaden the repertoire of available chemical modifications for siRNA therapeutics and imply potential regulatory role of N6-methyladenosine in the RNAi pathways.

Keywords: antisense agents; epigenetics; methyladenosine; oligonucleotides; siRNA.

MeSH terms

Adenosine / analogs & derivatives*
Adenosine / chemistry
Adenosine / genetics
Epigenesis, Genetic / genetics
Nucleic Acid Conformation
RNA, Small Interfering / chemistry*
RNA, Small Interfering / genetics

Substances

RNA, Small Interfering
N-methyladenosine
Adenosine