Phosphorothioate stereochemistry in therapeutic oligonucleotides

The idea that the stereochemistry of the phosphorothioate backbone modifications may influence the pharmacological properties of therapeutic oligonucleotides is not a new concept but has regained attention due to improvements in the synthesis of stereo-selective oligonucleotides1. Several recent papers have investigated this idea in antisense2, immunomodulatory3 and splice-switching oligonucleotides4 as well as siRNAs5. In general,…

Folate – the new kid on the block of oligonucleotide conjugates for targeted delivery?

According to a new paper by Orellana et al.1 this may well be the case. The paper mainly focuses on a folate-conjugated microRNA 34a mimic for the treatment of cancer, but a folate-conjugated Luc siRNA was also successfully delivered to and active in cells expressing the folate receptor (FOLR1). The FOLR1 ligand folate (vitamin B9)…

nucleic acid immunity

Nucleic acid immunity as relevant to oligonucleotide therapeutics

Under the constant selection pressure of infection by diverse and ever-changing pathogens, eukaryotic cells and organisms have evolved complex immune systems to defend themselves. Of particular interest for the oligonucleotide therapeutics field is the response of the innate immune system to the introduction of exogenous nucleic acids and how to bypass or manipulate this reaction…