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Medicinal Chemistry

Oligonucleotide synthesis gets an overhaul

Phosphorus(V) chemistry connects nucleosides for therapeutic applications

by Bethany Halford
September 13, 2021

The structures five reagents used to make various oligonucleotide connections.
Five reagents in a new platform for oligonucleotide synthesis make five different linkages between oligonucleosides.

A new platform for making oligonucleotides offers chemists a way to plug in five types of nucleoside connections, so they can tailor properties of oligonucleotide therapeutics. These short DNA or RNA molecules modulate gene expression to treat disease. The platform uses phosphorus(V) chemistry, which was once considered too sluggish to be practical for oligonucleotide synthesis. But the P(V) reagents developed for the platform have comparable reaction rates to the P(III) reagents typically used to synthesize oligonucleotides and can be used in standard oligonucleotide-making equipment.

The platform, developed by chemists at Bristol Myers Squibb and Scripps Research Institute California, expands on earlier work by the group to make chiral phosphorothioates—a linkage that’s common in oligonucleotide therapeutics, such as Spinraza, a spinal muscular atrophy drug from Ionis and Biogen. In addition to creating R and S phosphorothioate linkages, the platform includes reagents for making racemic phosphorothioates, phosphorodithioates, and native phosphodiesters—the type of oligonucleotide linkage found in DNA (Science 2021, DOI: 10.1126/science.abi9727).

“The idea is that you can take any of these linkages, any of these modifications, plug and play in whatever combination you want,” says BMS’s Ivar M. McDonald. McDonald led the development of the oligonucleotide-making platform with BMS colleagues Martin D. Eastgate and Michael A. Schmidt and Scripps’s Phil S. Baran.

“This is an extremely important contribution to the field of chemical nucleic acid synthesis,” says University of Greifswald’s Sabine Müller, an expert in making natural and modified oligonucleotides, in an email. “The new platform is of enormous importance for the production of therapeutic oligonucleotides on an industrial scale and has the potential to revolutionize this field,” she says. The new reagents were also recognized with a 2021 US Environmental Protection Agency Green Chemistry Challenge Award.

The phosphorus in oligonucleotide linkages exist as P(V), so starting out in that oxidation state cuts down the number of synthetic steps, McDonald explains, because the chemists don’t have to oxidize P(III).

Eastgate says that the team has spent the last three years working to control the reactivity of P(V), making slight tweaks to optimize each reagent. “Phosphorus(V) has very subtle reactivity to it,” he says. “One little change really affects how the molecule behaves and reacts.”

McGill University’s Masad J. Damha, who studies the chemical biology of nucleic acids, says in an email that the researchers “ought to be congratulated for inventing new reagents and protocols that bring P(V) chemistry back to life.” He points out that medicinal chemists and structural biologists will find the options for connecting nucleosides attractive for studying nucleic acid-protein interactions. “I look forward to having access to these reagents so we can all experiment with them,” he says.



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