Click Conjugation of targeting moieties enables active cell transport of Oligonucleotide drugs.
Oligonucleotide drug therapeutics are a potential drug class for wide range of diseases. With just 9 approved products they already generated more than. 2 billion dollars in sales 2019.[1] The main challenge with this class of drugs is that the target of the oligo is located inside the cell, which is difficult for a large, negatively charged molecule to reach. One possible way to overcome this problem is to bioconjugate molecules to an Oligo which are recognized by cell surface structure and induce active transport to the cell.
-No packaging of the Oligo/mRNA is needed with either negative polymers/ lipid nanoparticles or PEG structure which can cause allergic reaction.[2]
-Using of active cell transport enables the possibility to deliver your molecule to the right cell type e.g., liver cells [3].
Ability to target any possible gene in the genome, including targets that are till now „undruggable” by small molecules and antibodies (siRNA/RNAi).
Introduction of your targeting moiety via click Chemistry/SPAAC provides high yields in mild conditions to reduce RNA damages to a minimum for a cost-effective synthesis.
GalNAc conjugated Antisense Oligos need a 10-to 30-fold lower doses then the same non target ASO.[4]
Givosiran (alnylam) as first approved GalNAc based drug. Givosiran (alnylam) as first approved GalNAc based drug. Many more drugs based on targting moieties are being developed. [5]
The introduction of a Phosphorthioester backbone leads to increased stability in cell media. LNA is also increasing the stability and base-pairing properties which make it an ideal candidate for ASO molecules [6].
[1] https://doi.org/10.1016/j.ymthe.2020.06.015
[2] https://doi.org/10.1007/s40629-021-00165-7
[3] https://doi.org/10.1016/j.ymthe.2020.06.015
[4] Crooke, S.T., Baker, B.F., Xia, S., Yu, R.Z., Viney, N.J., Wang, Y., Tsimikas, S., and
Geary, R.S. (2019). Integrated assessment of the clinical performance of GalNAc 3-
conjugated 20-O-methoxyethyl chimeric antisense oligonucleotides: I. Human
volunteer experience. Nucleic Acid Ther. 29, 16–32.
[5] Alnylam Pharmaceuticals. Alnylam development pipeline of investigational RNAi therapeutics. https://www.alnylam.com/alnylam-rnai-pipeline/