Locked nucleic acid: modality, diversity, and drug discovery

Abstract

Over the past 20 years, the field of RNA-targeted therapeutics has advanced based on discoveries of modified oligonucleotide chemistries, and an ever-increasing understanding of how to apply cellular assays to identify oligonucleotides with improved pharmacological properties in vivo. Locked nucleic acid (LNA), which exhibits high binding affinity and potency, is widely used for this purpose. Our understanding of RNA biology has also expanded tremendously, resulting in new approaches to engage RNA as a therapeutic target. Recent observations indicate that each oligonucleotide is a unique entity, and small structural differences between oligonucleotides can often lead to substantial differences in their pharmacological properties. Here, we outline new principles for drug discovery exploiting oligonucleotide diversity to identify rare molecules with unique pharmacological properties.

Antisense Oligonucleotide in LNA-Gapmer Design Targeting TGFBR2—A Key Single Gene Target for Safe and Effective Inhibition of TGFβ Signaling

“…The mechanism of internalization is predominantly driven by endocytosis. Nonetheless, cellular uptake is a highly diverse and differentiated process that is dependent on many parameters, such as cell type, proliferation/cell cycle state, extracellular composition, oligonucleotide design/substitutions pattern, concentration, and phosphorothioate configuration [36,59,60]. Hence, no transfection agent is needed and potential additional adverse effects for patients might be avoided in clinical development, which is not always achieved [61].…”

From DNA Nanotechnology to Material Systems Engineering

“…Importantly, as demonstrated in proteomic studies, synthetic peptide nucleic acid (PNA) oligomers can as well be used for DDI. This draws attention to a generally important point: DNA‐based materials are increasingly produced with synthetic DNA analogs, e.g., PNA or locked nucleic acids (LNA), in order to increase physical and biological stability …”

Synthesis of 6′‐Methyl‐2′‐O,4′‐C‐methylene‐α‐L‐ ribofuranosyl‐pyrimidine Nucleosides

“…The sugar modifications, such as 2′‐F, 2′‐OMe and 2′‐ O ,4′‐ C ‐methylene bridge are being widely used to achieve the effectiveness of oligonucleotides . Structurally modified 2′‐ O ,4′‐ C ‐methyleneribofuranosyl‐nucleosides (LNA monomers) feature remarkable control over sugar‐ring puckering and therefore oligonucleotides derived from them have been extensively used as antisense oligonucleotides (ASOs) to modulate gene expression (Figure ) . Some of them have now entered into clinical trials for the treatment of diseases, such as infection of hepatitis C virus,, spinal muscular atrophy, prostate cancer, etc.…”