Flow process speeds up peptide synthesis

Nature makes amide bonds—the key linkages that string together amino acids in a polypeptide—like a knitting whiz. The ribosome in Escherichia coli bacteria, for example, can make eight amide bonds in a second. Chemists are novices by comparison, taking minutes to hours to form an amide bond in a flask.

These scientists are stepping it up, though; a group led by Bradley L. Pentelute of MIT has developed a fully automated flow approach to solid-phase peptide synthesis that can make an amide bond in seven seconds and assemble a peptide at a rate of 40 seconds per amino acid (Nat. Chem. Biol. 2017, DOI: 10.1038/nchembio.2318).

In solid-phase peptide synthesis, chemists grow a polypeptide chain on a polymer bead one amino acid at a time through cycles of amide-forming reactions. Pentelute and colleagues automated a 2014 manual flow system for such a process, resulting in an apparatus nicknamed “the Amidator.” It consists of a buffet of 50 solutions of different reagents, including natural and unnatural amino acids and chemical activators, hooked up to three pumps. The apparatus coordinates the reagents’ stoichiometry and controls when they are heated, all while the reagents are flowing along at 80 mL per minute.

The flow system is 10 to 100 times as fast as batch-based solid-phase peptide synthesis methods currently used, Pentelute says. If the Amidator worked nonstop for a year, it could create tens of thousands of peptides 30 amino acids long. “This really removes one of the bottlenecks to pushing chemical research forward,” Pentelute points out, “which is just the time it takes to get your hands on molecules.”