Biology

UK chemists have cracked a long-standing problem in peptide synthesis that has prevented amino acid chains being grown from both ends. The insight could open up efficient ways to make peptide-based drugs.

Lawrence Harwood and colleagues at the University of Reading say they have discovered a way to extend peptides from the carboxylic acid end without scrambling the stereochemistry - solving a problem that has stumped chemists for decades. The Reading team has now won a Ð'Ј63,000 grant for commercialisation of the technique, to license to companies working in the rapidly growing market of peptide-based drugs.

All peptides have a carbon terminus at one end, and a nitrogen terminus at the other. But because of issues with stereochemistry, chemists are currently limited to extending peptides from the nitrogen end.

"This is such a profound problem that the impossibility of synthesising peptides from the acid terminus has become dogma in the field"

- Lawrence Harwood

'Conventional peptide synthesis is always carried out in a very linear manner, building the peptide chain from the nitrogen terminus, as attempts to grow peptide chains from the acid terminus result in scrambling of the stereochemistry,' explains Harwood. 'This is such a profound problem that the impossibility of synthesising peptides from the acid terminus has become dogma in the field of peptide synthesis.'

However, Harwood is new to the peptide field. 'We weren't steeped in this dogma, and didn't realise this reaction shouldn't be able to happen, so we just went away and did it,' he adds. Harwood says the new technique could be used to make peptides more easily, because it means short peptides chains could be clipped together - freeing chemists from having to add amino acids one by one to the nitrogen end of the chain.

Stereochemical scrambling

Extending a peptide from the carboxylic acid end of the chain requires that the acid group is pre-activated, increasing its reactivity towards the incoming amino acid so that the new peptide bond will form. However, this activated intermediate can transiently react with itself, forming a cyclic oxazolone. This structure is prone to temporarily losing a hydrogen ion, mixing up the stereochemistry at that point.

Harwood says he has now overcome this issue, activating the C-terminus by converting it into a morpholine ring. 'We'd been studying these compounds for well over a decade, and for most of that time we'd been trying to suppress the labile nature of the morpholine ring to be opened by nucleophiles. Only two or three years ago, I sat down and thought, instead of making this a problem, could we use it to our advantage?' Harwood realised the morpholine