A more sustainable way to make DNA-based medications

Scientists at McGill University have developed a solvent-free method for making oligonucleotides, short strands of DNA of growing significance in research and the pharmaceutical industry.

Several oligonucleotide-based drugs have been approved for use in North America to treat conditions ranging from macular degeneration to genetically-related high cholesterol, and many more are in development. But existing processes for synthesizing oligonucleotides are energy intensive and rely on the use of environmentally harmful solvents. Masad Damha, a McGill chemistry professor who specializes in DNA- and RNA-based therapeutics, cites an example of a manufacturer using 12,000 litres of the hazardous solvent acetonitrile to make just a kilogram of DNA made up of 20 nucleotides.

Growing demand drives need for greener process

“That is an insane amount of solvent,” Damha says. “DNA (and RNA) are now firmly in the therapeutics stream of pharma, so it’s imperative to find alternatives to the processes used to make them. Market forecasts are for a demand on the scale of thousands of kilograms for rare and complex oligos, and likely 10 to 100 times that amount for more conventional oligos.”

Damha has teamed up with fellow McGill chemistry professor and green chemistry expert Tomislav Friščić to develop a mechanochemical process for producing oligonucleotides that maximizes yield and purity while minimizing harmful waste products.

Research problem smashed to bits

“Mechanochemistry, or chemistry through mechanical force, is a fancy way of saying ‘smashing things together’,” says Friščić of the grinding and milling techniques his lab has been perfecting over several years. “It allows us to think about chemical reactions without using solvents, with the ultimate aim of making the global chemical enterprise greener, by reducing or even completely eliminating the production of toxic solvent waste in research and industry.”

In results published in Chemistry—A European Journal, the research team successfully produced short chains of DNA two to three nucleotides in length using a solvent-free mechanochemical method. The researchers say their method is generally applicable to the synthesis of longer sequences, too, and is compatible with industrial-scale manufacturing techniques. Their approach to DNA synthesis is unique in that it combines three separate reactions into one.

“This is an interesting discovery from a chemistry point of view, but it also saves time and money that would otherwise be involved in purifying products after each individual reaction,” Damha says.

Funding for the research was provided by the McGill Sustainability Systems Initiative (MSSI) Innovation Fund and the Natural Sciences and Engineering Research Council of Canada (NSERC).

About the paper

“Mechanochemical Synthesis of Short DNA Fragments” by James D. Thorpe et al. was published in Chemistry—A European Journal.
DOI: https://doi.org/10.1002/chem.202001193

About the MSSI Innovation Fund

The MSSI Innovation Fund provides funding to move sustainability-focused projects to the next stage of development, from activities required for commercialization to policy development.

› Learn more about the McGill Sustainability Systems Initiative (MSSI)