A phosphorus(V) synthesis platform reported in 2021 gives researchers more control over the phosphate-backbone linkages in oligonucleotides, including the ability to combine different linkage types at selected positions. That could widen the design options for future therapeutic molecules, but the study demonstrated a chemistry method—not a new treatment or clinical benefit.
What makes an oligonucleotide “unusual”?
Oligonucleotides are short DNA or RNA molecules. Therapeutic versions are designed around a target sequence, but their chemical modifications also matter: the backbone linking their nucleotide units can be altered to influence properties such as target recognition and how a molecule behaves in the body. These are complementary design considerations, not guarantees that a particular modification will make a drug more effective.
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A common modification replaces one of the phosphate linkage’s non-bridging oxygen atoms with sulfur, producing a phosphorothioate linkage. The phosphorus atom in such a linkage can have different stereochemical configurations. A product containing a mixture of those configurations is described as racemic; a stereodefined product has a selected configuration, such as R or S.
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What did the phosphorus(V) method add?
Conventional oligonucleotide synthesis commonly uses phosphorus(III), or P(III), phosphoramidite chemistry. Huang and colleagues’ 2021 paper in Science describes a broader phosphorus(V), or P(V), platform that provides access to several phosphate-backbone choices:
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- Stereodefined phosphorothioates: linkages with a selected phosphorus configuration, including R or S.
- Racemic phosphorothioates: linkages produced as a mixture of stereoisomers.
- Phosphodiesters: the native phosphate linkage, without a sulfur substitution.
- Phosphorodithioates: linkages in which two non-bridging oxygen atoms are replaced by sulfur.
The platform’s central contribution is that these linkage types can be installed in selected combinations within a single oligonucleotide, creating chimeric backbones. This is expanded synthetic access: the paper does not show that every possible pattern is useful, or that a particular pattern improves a medicine.
How does it compare with established synthesis?
The new approach is best understood as an expansion of the available chemistry, not a replacement proven superior to established P(III) synthesis. P(III) phosphoramidite methods are mature, widely optimized, and effective for the structures they routinely produce. The differences reported in the 2021 study and contemporaneous coverage include:
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| Consideration | Established P(III) phosphoramidite chemistry | Reported P(V) platform |
|---|---|---|
| Phosphorus building blocks | Uses trivalent phosphorus building blocks. | Uses phosphorus(V) chemistry. |
| Water sensitivity | RNA-drug developer Punit Seth told Chemistry World that P(III) building blocks are sensitive to water. | The study describes P(V) reagents as stable; this is a reported characterization, not a head-to-head manufacturing assessment. |
| Control of phosphorothioate stereochemistry | Traditional phosphoramidite chemistry prepares phosphorothioate linkages as mixtures of stereoisomers, according to Bristol Myers Squibb’s Ivar McDonald. | Provides access to stereodefined phosphorothioates as well as racemic products. |
| Linkage options | The reported comparison focuses on the established approach’s capabilities and does not give a full catalogue of linkage types. | Reported access to phosphorothioates, phosphodiesters, and phosphorodithioates, including selected combinations. |
| Automation and reaction time | The P(III) approach is described as highly optimized, but the report gives no comparable conversion-time figure. | Chemistry World reported compatibility with automated protocols and full conversion in under two minutes for the reactions in the study’s comparison. |
| Manufacturing maturity | Methods and supply chains are highly optimized, according to the study’s researchers. | A newer platform whose transition into routine manufacturing would require adoption and validation. |
The under-two-minute result applies to the reported reactions, not every sequence, instrument, or production setting. Likewise, reported automation compatibility does not by itself establish large-scale manufacturing performance.
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An oligonucleotide’s sequence and its backbone chemistry can contribute differently to properties relevant to therapeutic design. Being able to choose linkage type and phosphorus stereochemistry at specific positions gives researchers additional variables to investigate when tuning a molecule. The value of that flexibility depends on what testing shows for each design; synthesis access alone cannot establish improved target activity, pharmacokinetics, safety, or clinical performance.
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Does this method already make a gene therapy treatment?
No. The 2021 Science paper reports a synthesis platform, not a clinical trial of a medicine made with it. The paper’s introduction said that more than 155 active clinical trials and multiple U.S. Food and Drug Administration approvals for therapeutic oligonucleotides existed at that time. That is a historical figure published in 2021, not a current count, and it does not show that products made with this specific method were approved or tested in those trials.
The study therefore supports a possibility: broader control over oligonucleotide chemistry may help researchers explore future drug designs. It does not establish that this method treats disease, produces an approved medicine, or improves patient outcomes.
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What remains between a chemistry result and routine use?
The platform was described as using a standardized coupling protocol, with reagents that the paper characterized as sustainably prepared and stable. Chemistry World reported that the team was working with Millipore-Sigma in 2021 to make reagents commercially available. That report is historical and does not establish current product availability.
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Routine adoption also has practical hurdles. Existing P(III) methods and supply chains already work well for established applications, so switching or adding a platform involves more than demonstrating a reaction. Researchers and manufacturers would need to validate the chemistry for relevant sequences, workflows, and production requirements. The 2021 report quoted Bristol Myers Squibb’s Ivar McDonald recognizing that a change would not happen overnight.
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Sources
- Huang et al., “A phosphorus(V)-based platform for oligonucleotide synthesis,” Science, 2021.
- Chemistry World’s 2021 report on the method.
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