Peptide synthesis and flow chemistry

In early 2017, I spent two weeks working off site with a collaborator, New Path Molecular Research, helping to develop what would become Vapourtec’s peptide synthesis platform. Crikey what a project it was, talk about fascinating! The overall concept is deceptively simple, as all good concepts are really; you start with some form of solid support, typically some derivative of a Merryfield resin, attach the first amino acid of your peptide sequence to it, and then just keep adding on the right amino acids until your sequence is finished. Chemically detach the end from the support and hey presto! Your nice and clean peptide is ready to use.

The technical challenge was a little more complex, but flow chemistry is ideal for this procedure; batchwise solid-phase peptide synthesis (SPPS) is, frankly, fiddly. Every amino acid you want to add, you first have to deprotect the terminal amino acid already in the sequence, wash and dry. Add the next amino acid and give it sufficient time to react, wash and dry. Deprotect again, wash and dry and so it goes on until your sequence is finished. Each step can take hours in total, and three or four couplings a day is about the best you can hope for. The advantage that flow brings immediately is that the resin is being constantly washed, merely by virtue of being in flow. So that step of the process is now redundant. Also, in flow we can easily pre-activate our amino acids, usually to an ester, so the coupling is fast; this can be done in batch too, but the activated species must be used quickly, otherwise it can racemise or decompose. In flow we can pre-activate the amino acid quickly and pass it immediately over the deprotected sequence on the resin.

The new platform is complex, it’s probably the most advanced Vapourtec configuration I’ve worked on but with that complexity comes some impressive capability (which can be read about in detail here). Automated liquid handlers let you dial in the sequence you need, and inline spectroscopic and physical measurements allow real-time monitoring of the efficiency of each coupling, and if a coupling hasn’t worked properly? Run it again. As long as the newly added amino acid is not deprotected first, you can only build the sequence that you want.

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