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Oligonucleotide Synthesis for Therapeutics |
Oligonucleotide therapeutics are an up-and-coming class of drugs comprised of short DNA and/or RNA molecules that modulate the expression of target RNA for the treatment of diseases. Common types of oligonucleotide therapeutics include antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs) involved in RNA interference (RNAi), small activating RNAs (saRNAs), aptamers, and guide RNAs (gRNAs) involved in CRISPR gene editing technology. (Infographic: Oligonucleotide therapeutics)
The industry-wide standard for oligonucleotide synthesis is by chemical reactions using phosphoramidites as the building blocks. DNA or RNA oligo manufacturing begins with designing an oligo of a specific nucleic acid sequence (with modifications as needed), to chemically synthesize, purify, and analyze. This is followed by formulation and production for its specific application. Automated oligo synthesizers complete sequential chemical reactions using phosphoramidites to produce the nucleotide chains of synthetic oligos.
![]() | Quality and scalability—Phosphoramidites used for therapeutic applications must be produced under a refined quality system (e.g., ISO 9001:2015) with extensive testing for consistency, purity, traceability, and stability, to help meet requirements set by regulatory bodies. In addition, manufacturing must be scalable, especially when a therapeutic is ready to go into clinal trials and eventually, manufacturing. |
![]() | Common modifications—Because of their therapeutic uses, phosphoramidites are often modified to increase nuclease resistance and thermal stability while lowering their immunogenicity. Such modifications include 2′-O-methyl (2′-OMe), 2′-O-methoxy-ethoxy (2′-MOE), and 2′-fluoro (2’-FL). For delivery to target organs, conjugating moieties such as N-acetylgalactosamine (GalNAc) to the oligos for uptake (e.g., in the liver, by hepatocytes) is a common approach. |
![]() | Critical impurities—Controlling impurities that can be generated during phosphoramidites synthesis is critical to the development of your therapeutic. The presence of reactive and critical impurities can be limited through manufacturing processes implemented by phosphoramidite suppliers, such as rigorous control of raw material specifications, in-process manufacturing controls and testing, and final release testing. ( Tech note: Classification and characterization of impurities in phosphoramidites used in making therapeutic oligonucleotides) |
Thermo Fisher Scientific offers a broad portfolio of phosphoramidites specifically designed for therapeutics applications. Our Thermo Scientific TheraPure phosphoramidites undergo additional quality control release testing and are compared with our standard phosphoramidites, helping to ensure that impurities and residual solvents are controlled to the stringent levels required by our customers for their oligo therapeutics.
Our TheraPure phosphoramidites are supported by:
Processes are monitored from material procurement through final QC and product release for batch-to-batch reproducibility. Purity of each phosphoramidite lot is assessed by HPLC-MS, GC, 31P NMR, as well as the Karl Fischer method. Our rigorously controlled manufacturing processes help minimize levels of reactive P(III) impurities which could be incorporated into the oligonucleotide during synthesis and result in the accumulation of by-products.
Designed specifically to help meet the needs in oligonucleotide synthesis for therapeutic applications, our TheraPure phosphoramidites are available in DNA, RNA, and 2′ modifications. For additional options, please inquire us so that we can explore possibilities with you.
Find phosphoramidites with deoxyribonucleobases for synthesis of DNA oligos for therapeutic applications.
Find phosphoramidites with ribonucleobases for synthesis of RNA oligos for therapeutic applications.
Find modified phosphoramidites such as 2′-MOE, 2′-OMe, and 2′-fluoro for synthesis of ASOs, siRNAs, gRNAs, etc. for therapeutic applications.
For additional phosphoramidites (e.g., dye-labeled, structural, linkers, spacers), please visit here
In addition to our Thermo Scientific phosphoramidites, we offer custom services for oligonucleotide chemistry to tailor to your therapeutic applications. We are fully set up to provide customization of our existing phosphoramidites, synthesis of new compounds, and development of oligonucleotide delivery chemistries. Simply fill out this short form with your interest so that our representative can explore available options with you.
Phosphoramidite customization options
A. Dimethoxytrityl (DMT) substitution with alternate protecting groups
B. Base = A, C, G, T, or U protection modifications or base modifications
C. Sugar modifications and protection options
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