The chemical evolution of oligonucleotide therapies of clinical utility

UMMS Affiliation

RNA Therapeutics Institute; Program in Molecular Medicine; Department of Biochemistry and Molecular Pharmacology

Publication Date


Document Type



Biochemistry | Biotechnology | Chemicals and Drugs | Medicinal Chemistry and Pharmaceutics | Therapeutics


After nearly 40 years of development, oligonucleotide therapeutics are nearing meaningful clinical productivity. One of the key advantages of oligonucleotide drugs is that their delivery and potency are derived primarily from the chemical structure of the oligonucleotide whereas their target is defined by the base sequence. Thus, as oligonucleotides with a particular chemical design show appropriate distribution and safety profiles for clinical gene silencing in a particular tissue, this will open the door to the rapid development of additional drugs targeting other disease-associated genes in the same tissue. To achieve clinical productivity, the chemical architecture of the oligonucleotide needs to be optimized with a combination of sugar, backbone, nucleobase, and 3'- and 5'-terminal modifications. A portfolio of chemistries can be used to confer drug-like properties onto the oligonucleotide as a whole, with minor chemical changes often translating into major improvements in clinical efficacy. One outstanding challenge in oligonucleotide chemical development is the optimization of chemical architectures to ensure long-term safety. There are multiple designs that enable effective targeting of the liver, but a second challenge is to develop architectures that enable robust clinical efficacy in additional tissues.

DOI of Published Version



Nat Biotechnol. 2017 Mar;35(3):238-248. doi: 10.1038/nbt.3765. Epub 2017 Feb 27. Link to article on publisher's site

Journal/Book/Conference Title

Nature biotechnology

Related Resources

Link to Article in PubMed

PubMed ID