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Solid-phase peptide synthesis (SPPS) and native chemical ligation (NCL) are powerful methods for obtaining peptides and proteins that are otherwise inaccessible. Nonetheless, numerous sequences are difficult to prepare via SPPS, and cleaved peptides often have low aqueous solubility. To address these challenges, we developed a "Synthesis Tag" consisting of six arginines connected to the target sequence via a cleavable MeDbz linker. "SynTag" effectively improves batch- and flow-SPPS of "difficult sequences", enhances the solubility of the cleaved peptides, and provides direct access to native sequences by hydrolysis, or peptide thioesters for NCL. We demonstrate its utility in the first chemical synthesis of the MYC transactivation domain with a single NCL. We envisage SynTag to become a broadly applicable tool that enables the synthesis and study of previously unattainable peptides and proteins.

Flow chemistry has emerged as a powerful method for on-demand chemical synthesis and modification of peptides and proteins. Herein, we discuss the characteristics of flow chemistry and how they are applied to various aspects of peptide chemistry. We highlight recent advances in automated flow-based peptide synthesis, which extend the length of peptides routinely accessible to single-domain proteins and allow for the collection of time-resolved synthesis data. Applications of this data for the prediction of synthesis outcome and the potential for the development of more sustainable synthesis methods are also discussed. Finally, we will review solutionphase approaches, including flow-based ligation strategies and peptide cyclization. Throughout this review, the current challenges and potential future developments are highlighted.

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., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The 8 th Chemical Protein Synthesis meeting took place in Berlin in June 2019, covering broad topics in protein chemistry, ranging from synthetic methodology to applications in medicine and biomaterials. The meeting was also the culmination of the Priority Program SPP1623 on "Chemoselective Reactions for the Synthesis and Application of Functional Proteins" funded by the German Science Foundation (DFG) from 2012 to 2018. We present highlights from presentations at the forefront of the field, grouped into broad themes that illustrate how the field of protein chemistry is looking ahead to new discoveries and applications., (Copyright © 2019.)