Refining LNA safety profile by controlling phosphorothioate stereochemistry
Erik Daa Funder1, Nanna Albæk1, Annie Moisan2
1Roche Innovation Center Copenhagen A/S, Hørsholm, Denmark.
Plos One
|June 13, 2020
Summary
Stereochemistry control in phosphorothioate LNA oligonucleotides enhances safety and therapeutic index. This advancement in drug discovery improves safety without reducing efficacy in target mRNA knockdown.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Molecular Biology
Background:
- Phosphorothioate oligonucleotides are crucial in drug discovery.
- LNA oligonucleotides offer therapeutic potential.
- Stereochemistry of the phosphorothioate backbone is a key factor.
Purpose of the Study:
- Investigate the impact of controlled stereochemistry on LNA oligonucleotide properties.
- Evaluate safety profile, target mRNA knockdown, and cellular uptake.
- Determine if stereochemical control can enhance the therapeutic index.
Main Methods:
- Synthesized LNA oligonucleotides with controlled stereochemistry at four key backbone positions.
- Performed in vitro assays to assess cellular uptake.
- Quantified target mRNA knockdown efficiency.
- Evaluated the safety profile of the modified oligonucleotides.
Main Results:
- Controlling stereochemistry in the phosphorothioate backbone significantly improved the safety profile.
- Enhanced safety was achieved without compromising target mRNA knockdown activity.
- Cellular uptake remained comparable across different stereoisomeric forms.
- The therapeutic index was significantly improved due to enhanced safety.
Conclusions:
- Stereochemical control of the phosphorothioate backbone is a viable strategy for improving LNA oligonucleotide therapeutics.
- This approach offers a way to enhance drug safety without sacrificing efficacy.
- Further development of stereochemically pure oligonucleotides holds promise for drug discovery.
