The Medicinal Chemistry of Therapeutic Oligonucleotides

Abstract

Oligonucleotide-based therapeutics have made rapid progress in the clinic for treatment of a variety of disease indications. Unmodified oligonucleotides are polyanionic macromolecules with poor drug-like properties. Over the past two decades, medicinal chemists have identified a number of chemical modification and conjugation strategies which can improve the nuclease stability, RNA-binding affinity, and pharmacokinetic properties of oligonucleotides for therapeutic applications. In this perspective, we present a summary of the most commonly used nucleobase, sugar and backbone modification, and conjugation strategies used in oligonucleotide medicinal chemistry.

Discovery of Key Physicochemical, Structural, and Spatial Properties of RNA‐Targeted Bioactive Ligands

“…To focus on small organic molecules, peptides and oligonucleotides were omitted. [12] Aminoglycosides were excluded due to known promiscuous RNA-binding behavior. [10c, 11b, 13] Molecules satisfying the selection criteria and highlighted in the conclusion of each report were included in the R NA - targeted BI oactive liga N d D atabase (R-BIND) (available as RBIND.xls).…”

Triplex- and Duplex-Forming Abilities of Oligonucleotides Containing 2′-Deoxy-5-trifluoromethyluridine and 2′-Deoxy-5-trifluoromethylcytidine

“…1,2) In particular, artificial oligonucleotides with high binding affinity towards double-stranded DNA (dsDNA) and single-stranded RNA (ssRNA) can be applied to antigene and antisense technologies. Therefore, chemical modifications of nucleobase, sugar and phosphate moieties have been investigated.…”

RNA Therapeutics in Oncology: Advances, Challenges, and Future Directions

“…There have been several recent reviews describing in detail the chemical approaches to overcoming the nuclease sensitivity of single-stranded RNA therapeutic, and double-stranded siRNAs. 26,27 The substitution of sulfur for oxygen to generate phosphorothiate (PS) internucleotide linkages is the most common and most effective means to date to stabilize nucleic acid molecules against nucleasemediated degradation. 28 In addition to increased nuclease resistance, PS linkages also greatly increase the binding of nucleic acids, particularly single-stranded nucleic acids (ASOs, miRNAs) to serum proteins (principally albumin) leading to prolonged circulation in plasma, decreased clearance by the kidney enhanced compartments where the molecular mechanisms of action are invoked, which are principally the nucleus for ASO-and miRNA-based therapeutics and the cytoplasm of cells for siRNA inhibitor.…”