Research Article

Synthesis of proteins by automated flow chemistry

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Science  29 May 2020:
Vol. 368, Issue 6494, pp. 980-987
DOI: 10.1126/science.abb2491

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Fully synthetic whole proteins in reach

Solid-phase peptide synthesis of homogeneous peptides longer than about 50 amino acids has been a long-standing challenge because of inefficient coupling and side reactions. Hartrampf et al. used an automated chemistry platform to optimize fast-flow peptide synthesis and were able to produce fully synthetic single-domain proteins (see the Perspective by Proulx). The targets included proinsulin and enzymes such as barnase and a version of HIV-1 protease containing multiple noncanonical amino acids. Refolded peptides were nearly indistinguishable from recombinant proteins, and the synthesized enzymes had activity close to that of their ribosomally synthesized counterparts. This method will enable fast, on-demand synthesis of small proteins with a vastly expanded pool of precursor amino acids.

Science, this issue p. 980; see also p. 941


Ribosomes can produce proteins in minutes and are largely constrained to proteinogenic amino acids. Here, we report highly efficient chemistry matched with an automated fast-flow instrument for the direct manufacturing of peptide chains up to 164 amino acids long over 327 consecutive reactions. The machine is rapid: Peptide chain elongation is complete in hours. We demonstrate the utility of this approach by the chemical synthesis of nine different protein chains that represent enzymes, structural units, and regulatory factors. After purification and folding, the synthetic materials display biophysical and enzymatic properties comparable to the biologically expressed proteins. High-fidelity automated flow chemistry is an alternative for producing single-domain proteins without the ribosome.

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