Oligonucleotides are specially designed sequences of nucleotides,
which can be used as antisense oligonucleotides (ASOs), small interfering RNA (siRNA), microRNA (miRNA), aptamers, etc. Oligonucleotides can hybridize with target gene mRNA or pre-mRNA through complementary base pairing and modulate gene expression via various processes, including RNA interference (RNAi), target degradation through RNase H-mediated cleavage, splicing modulation, non-coding RNA inhibition, gene activation, and programmed gene editing. |
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| The application of oligonucleotides as therapeutic agents is a groundbreaking departure from the traditional small molecule inhibitors. With the capability to selectively target virtually any gene or protein expression, including those previously deemed “undruggable”. This has fueled excitement for their use in treating cancer, cardiovascular diseases, and rare conditions. To date, regulatory bodies have approved 15 oligonucleotide drugs for various diseases. |
| Table 1. Approved oligonucleotide therapeutics[1][2]. |
| Aptamers |
| Drug Name |
Target |
Indication |
FDA Approval |
| Pegaptanib |
VEGF-165 |
Neovascular age-related macular degeneration |
2004
(Withdrawn) |
| Mixture of DNA |
| Drug Name |
Target |
Indication |
FDA Approval |
| Defibrotide |
NA |
Hepatic veno-occlusive disease |
2016 |
| ASOs |
| Drug Name |
Target |
Indication |
FDA Approval |
| Fomivirsen |
HCMV |
Cytomegalovirus retinitis |
1998
(Withdrawn) |
| Mipomersen |
APOB |
Homozygous familial hypercholesterolaemia |
2013
(Withdrawn) |
| Nusinersen |
SMN2 |
Spinal muscular atrophy |
2016 |
| Eteplirsen |
DMD
(exon 51) |
Duchenne muscular dystrophy |
2016 |
| Inotersen |
TTR |
Hereditary transthyretin amyloidosis; polyneuropathy |
2018 |
| Golodirsen |
DMD
(exon 53) |
Duchenne muscular dystrophy |
2019 |
| Volanesorsen |
APOC3 |
Familial amyloid neuropathies and familial chylomicronemia |
2019 |
| Viltolarsen |
DMD
(exon 53) |
Duchenne muscular dystrophy |
2020 |
| Casimersen |
DMD
(exon 45) |
Duchenne muscular dystrophy |
2021 |
| siRNAs |
| Drug Name |
Target |
Indication |
FDA Approval |
| Patisiran |
TTR |
Hereditary transthyretin amyloidosis; polyneuropathy |
2018 |
| Givosiran |
ALAS1 |
Acute hepatic porphyria |
2019 |
| Inclisiran |
PCSK9 |
Atherosclerotic cardiovascular disease; hypercholesterolemia |
2020 |
| Lumasiran |
HAO1 |
Primary hyperoxaluria type I |
2020 |
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| Therapeutic oligonucleotides are chemically modified to enhance in vivo applications. Modifications such as phosphorothioate DNA, phosphorodiamidate morpholino oligomers (PMO), and peptide nucleic acid designs lead to increased nuclease resistance and cellular uptake, thereby enhancing the efficacy of oligonucleotides. Tricyclic DNA (tcDNA), a conformationally constrained DNA analog, exhibits enhanced efficacy and tissue uptake following systemic administration. Ribose modifications (including 2ʹ-O-methyl (2ʹ-OMe), 2ʹ-O-methoxyethyl (2ʹ-MOE), and locked nucleic acids) are often combined to further improve stability, enhance target binding, and typically have lower toxicity compared to their non-modified counterparts[3]. |
| MedChemExpress — Master of Bioactive Molecules |
|
| MedChemExpress (MCE) stands out with its expert team and cutting-edge facilities for oligonucleotide synthesis and analysis. Capable of producing a variety of oligonucleotides (ASOs, siRNAs, miRNAs, aptamers and CpG ODNs, etc) tailored to customer’s specifications, MCE conducts thorough testing procedures (purity, structure, and stability analysis), and ensure the accuracy and reproducibility of data with high-quality and efficient services. |
References:  |
[1] Nat Rev Drug Discov. 2020;19(10):673-694.
[2] Pharmaceutics. 2022;14(2):260.
[3] Nat Rev Neurol. 2018;14(1):9-21. |
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