Abstract
Drug discovery with phosphorothioate oligonucleotides is an area of intensive research. In this study we have controlled the stereochemistry of the phosphorothioate backbone of LNA oligonucleotides to investigate the differences in safety profile, target mRNA knock down, and cellular uptake in vitro. The study reveals that controlling only four stereocenters in an isomeric phosphorothioate mixture can improve the therapeutic index significantly by improving safety without compromising activity.
MeSH terms
-
Animals
-
Cell Survival
-
Cells, Cultured
-
Chemistry, Pharmaceutical
-
Epithelial Cells / metabolism
-
Hepatocytes / metabolism
-
Humans
-
Kidney Tubules / metabolism
-
Mice
-
Molecular Structure
-
Oligonucleotides / administration & dosage
-
Oligonucleotides / chemistry*
-
Oligonucleotides / toxicity
-
Phosphorothioate Oligonucleotides / chemistry
-
RNA, Messenger / antagonists & inhibitors
Substances
-
Oligonucleotides
-
Phosphorothioate Oligonucleotides
-
RNA, Messenger
-
locked nucleic acid
Grants and funding
EDF, NA, AM, SS, and TK are or have been employees of Roche Innovation Center Basel or Roche Innovation Center Copenhagen A/S, F. Hoffmann-La Roche Ltd. The funder provided support in the form of salaries for authors [EDF, NA, AM, SS, and TK], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.