Sub-stoichiometric peptide synthesis

Solid-phase peptide chemistry is more than sixty years old. Its advent revolutionized peptide science. Innovation has increased safety and expanded the range of chemistries available to the practitioner, but the fundamental basis of the technology, the ability to easily wash away the required excess of amino acids needed to obtain quantitative conversion to avoid deletion sequences that complicate purification remains unchanged. It also masks a limitation: we must use super-stoichiometric amounts of amino acids, designing-in waste as part of our process. When using natural amino acids, readily and inexpensively available on large scale with Fmoc and appropriate orthogonal side chain protection, this is not a significant issue. When using a custom-made residue, “wasting” 60-90% of your valuable material becomes a scientific tragedy. This is no longer inevitable; we report that variable bed flow reactors allow for the high-purity synthesis of peptides, exemplified in up to 30mers, using less than one equivalent of amino acid per active amine group on the resin bed. By avoiding wasting amino acid building blocks, this technology likely represents the most significant effort to date in both reducing the environmental footprint and reducing the economic cost of peptide synthesis since Merrifield’s innovation in 1963.

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