Service with a smile

Contract organic synthesis is a competitive business. Service companies in China and India offer their skills at prices it can be difficult for western firms to compete with, and even though their prices are now rising, it can be difficult to persuade customers to look past the bottom line. So how does a company stand out from the crowd?

‘What we have on our side are communication and speed,’ says Mike McKenzie, head of operations at Charnwood Molecular, which has labs in Loughborough and Nottingham, UK. ‘We’re a global company that can respond quickly, and there’s no delay with things like shipping and getting things through Customs.’

But perhaps Charnwood’s biggest differentiator is its recent collaboration with French biotech firm Hybrigenics. With funding from the Eurostars programme, the two companies have developed a unique method for looking at how small molecules bind to proteins.

Baiting the trap

The Yeast-Chemical-Hybrid (YChemH) system links protein binding to genetic transcription machinery in modified yeasts, explains Charnwood’s Sylvain Blanc. The yeast is cultured in the absence of key amino acid histidine, so will only grow if its own histidine synthesis genes are expressed. Hybrigenics has developed a way to build libraries of potential target protein fragments (the ‘prey’) fused to the transcription factors that turn on those genes, as well as a set of anchor proteins that bind to the appropriate sequences of DNA to hold the transcription machinery in place.

To actually turn on transcription, the DNA-binding anchor protein needs to be joined up to the transcription factors. That’s where the small molecules come in. Charnwood takes the molecule of interest and links it to an appropriate molecule to bind to the anchor protein. This then acts as ‘bait’ for the prey proteins attached to the transcription machinery. When the bait molecule binds to its prey, it activates transcription and the yeast grows, giving an easy way to link molecules to their targets.

‘The anchor we use, the length and type of linker, and the site and method of how we join it to the bait molecule can all have an effect on how successful the screening is,’ says Blanc. The two companies will consult with clients to work out the best options for each molecule, then repeat the screen a few times with different linkers and attachment sites.

The big advantage of the YChemH system is that it can be used for a variety of purposes. ‘If you know a molecule is active but not how it works, we can identify the target that gives it its activity,’ says Blanc. ‘But we can also identify any off-target binding that might lead to side effects. We can look for new targets to repurpose existing drugs.’ There are chromatographic and mass spectroscopy-based methods for doing the same kind of thing, but they are expensive and take much longer, he adds.

Flexible friends

Charnwood was originally spun out from Loughborough University by Steve Allin (now at Nottingham Trent University) and Philip Page (now at the University of East Anglia). The business focused on polymer-supported catalysts, but soon progressed to offer contract synthesis services. In 2012, the company expanded into laboratory space in Nottingham’s BioCity small business incubator. ‘I used to work in this building when it was Boots pharmaceuticals, so it’s nice to come back,’ says Paul Bradley, site leader at Nottingham and head of medicinal chemistry.

Being in BioCity has significant advantages, explains Bradley. ‘We have flexible lab space, so if we take on a big contract we can expand very easily, but we don’t have to keep it running when we’re not using it.’ Charnwood can also take advantage of shared facilities within the complex, and make the most of the specialist services - such as chiral separations and biological screening - offered by other partner companies onsite.

The ever-changing flow of different projects keeps Charnwood’s chemists on their toes. ‘We’ve ended up working with all sorts of companies, some of whom we never thought would do chemistry,’ says McKenzie. ‘Our expertise in synthetic organic chemistry and medicinal chemistry makes us a valuable partner to support discovery research in life science companies. But we also provide our synthetic services to many other industries, from fragrances to photoelectronics.’