Tide turns for microwave chemistry

There is a lot more to microwave technology than the simple convenience of reheating yesterday’s takeaway.

In the field of chemistry, researchers are applying its unique capabilities to early-stage drug discovery, most notably in the field of peptide synthesis.

Typically, researchers turn to microwave instruments when they are conducting laboratory-scale work with small quantities of compounds, such as peptide research aimed at creating a new breed of more organically-based treatments for cancer or other diseases.

“In a laboratory, you can end up with a PhD chemist spending hours on manual tasks, so this technology can really increase the overall efficiency of your workforce

CEM product manager Michael Karney

“You can get a much greater speed in the research phase than you might with more conventional methods,” says Laurent Caron, operations manager at Cambridge Research Biochemicals (CRB).

CRB is a peptide and antibody manufacturer servicing the early stage of drug discovery, manufacturing research-grade material.

“Research has progressed and reagents are now available to make more complex and elaborate peptides,” says Caron.

“Microwaves really suit this type of development because, for more complex peptides, they can accelerate synthesis. This means medium-sized peptides can be made overnight,” he adds.

In spite of its benefits, some laboratories have steered away from microwave chemistry because they are either unfamiliar with the science or concerned about unwanted reactions such as racemisation, caused by heating some peptides during synthesis.

This process can switch some natural amino acids to their mirror image, “which may form a non-negligible amount of an impurity that might be more or less biologically active,” says Caron.

It can, however, be fairly simply overcome by lowering temperature and using less microwave power at key stages.

“Vendors have come up with certain cycles or programmes on their machines to lower the temperature when incorporating some of the amino acids,” he says.

Overall, the largest barrier to the adoption of microwave chemistry is cultural, says Michael Karney, product manager for the life sciences division of CEM Corporation, a microwave synthesis and medicinal chemistry specialist.

“This is caused by entrenched ideas about synthetic peptide chemistry and high temperature reactions,” he says.

“Peptide chemists are very well versed in room temperature chemistry; this has been the tried and true standard for years now.”

But he argues that rather than mastering new techniques, chemists simply need to integrate a few simple work arounds to prevent unwanted reactions and then realise the huge boost in efficiency microwave chemistry can offer.

“In a laboratory, you can easily end up with a PhD chemist spending hours and hours on manual tasks, so this technology can really increase the overall efficiency of your workforce,” Karney says.

Microwave chemistry will allow them to quickly create long or structurally diverse peptides and it can also be applied to peptidomimetics, which are structurally similar to peptides but not actually made of amino acids.

According to Karney, the biggest driver for the microwave peptide synthesis market is the growing commercial interest in peptide drugs.

“This results from some of the regulatory and market success of current peptide drugs which has helped guide the shifting pharmaceutical focus from small molecules to biologics,” he says.

But its potential to scale-up to intermediate research or even pre-production of complex peptides is one the biggest challenges and opportunities facing microwave chemistry, says Karney.

“With peptide synthesis, when you started to scale-up, microwave wasn’t the best solution. The first generation instruments could not accommodate the throughput required for general industrial applications. But we are now reaching the threshold of being relevant for pre-clinical scales of peptide synthesis,” he says.

To achieve this, the company released its Liberty Blue automated microwave peptide synthesiser about 18 months ago.

“We developed this product in conjunction with our high efficiency solid phase peptide synthesis (HE-SPPS) methodology which was published in a peer reviewed journal earlier this year,” says Karney.

This has “changed the conversation for microwave and with new methods have drastically increased efficiency of an already efficient method,” he adds.

CRB trialled the Liberty Blue earlier this year, and Caron says it was able to reduce the time of an overnight process to “just a couple of hours”.

Karney says the next step is to apply CEM’s experience to the pre-production scale with “a semi-automated microwave peptide synthesiser which is capable of chemistry at the 400 mmol (millimole) scale while rapidly completing cycles with the same high purity syntheses we demand of the Liberty Blue”.

This product, the Liberty XL, is expected to be released later in 2015.

“We think it will revolutionise the industrial scale synthesis of peptides just as the Liberty Blue has revolutionised the research scale,” he says.