First auto carbohydrate synthesiser

Nina Notman/Salt Lake City, US

German researchers have unveiled the first fully automated carbohydrate synthesiser, which they hope will advance development of carbohydrate-based vaccines for the developing world.

The new machine was announced at this week’s meeting of the American Chemical Society in Salt lake City, Utah, and could significantly reduce the amount of time it takes for researchers to build complex carbohydrates for vaccine research. Currently, synthesis of multiple carbohydrates for screening causes a bottle neck in efforts to discover new carbohydrate-based vaccines. 

’A chemical synthesis of a single carbohydrate typically takes months to years,’ explains Peter Seeberger from the Max Planck Institute of Colloids and Interfaces, Potsdam. His team has now revealed a next generation synthesiser, building on an earlier partially automated model announced in 2001, that Seeberger says is ’entirely reliable, very fast and can be operated by somebody with no experience of chemistry at all’. And when he says fast, he means fast: ’we have repeated a synthesis of a carbohydrate that initially took two years in the lab in less than 20 hours.’ He also claims to have fixed protection and deprotection issues, major hurdles in carbohydrate synthesis, that plagued the earlier version of the synthesiser.

The concept of the machine is very simple, solid phase chemistry. The starting point is a polystyrene bead with a single sugar attached and ’we add to that one sugar at a time like threading beads on a necklace,’ explains Seeberger. ’The bead’s only role is to stop the sugar from being dissolved, and using this methodology we can build up chains between six and 15 sugars. The addition of each sugar takes about two hours, meaning that in 1.5 to two days we can make pure, useable quantities of carbohydrates.’ In a single run they can make 25-50mg of carbohydrate. Seeberger also claims that the sugar building blocks can be made easily in 50-100g bulk quantities.

Carbohydrates surround every cell in humans, bacteria and viruses and play a crucial role in the body’s immune response to disease-causing viruses and bacteria. They have been used for medicinal purposes before, including in some blockbuster vaccines used to inoculate small children against bacterial diseases, such as meningitis, explains Seeberger. The current vaccines are based on isolated carbohydrates - meaning drug companies have to grow bacteria, harvest the carbohydrates, isolate mixtures of compounds and put them into a carrier protein - and Seeberger is looking to simplify this process by using carbohydrates that can be chemically synthesised and therefore help drive down the cost of these vaccines.

The 2001 version of his machine was used to develop a carbohydrate-based vaccine for malaria, scheduled to enter clinical trials in 2010. Malaria kills two million children a year in the developing world, explains Seeberger, and ’we have a cost target of under $1 per child’. Using their technique the team now have ’approximately 15 carbohydrates that are entering different phases of development for potential clinical purposes such as tuberculosis.’ 

The price is pretty attractive too - according to Seeberger the machine itself will cost somewhere in the region of $25,000 (?17,000), approximately one quarter the price of the analogous peptide synthesiser owned by most labs.

Geert Jan Boons, University of Georgia, Athens, US, an expert in carbohydrate synthesis, says that this technology is ’very sophisticated and has great potential’. Explaining that there is nothing similar available, he says ’most complex carbohydrates are made in solution, and any solid phase chemistry that is done uses manual approaches - where you add the reagents one by one yourself.’ Seeberger’s fully automated system handles everything, including cooling and warming of each step as required, he adds. Boons does however say that he is not entirely convinced that the chemistry is yet robust enough to make every type of carbohydrate, but adds that Seeberger does claim to have fixed these issues in research he is yet to publish. ’I think the biggest hurdle will be when he tries to make a bigger molecule,’ he explains, adding that the separation of the desired product from its isomeric compounds is another hurdle that needs to be overcome.