Abstract
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.
Highlights
Peptides, proteins, and derivatives thereof can be used as therapeutics and provide tools to investigate biological mechanisms at the molecular level, and their efficient production is of key interest for academia and the pharmaceutical industry
Flow chemistry has emerged as a powerful method for on-demand chemical synthesis and modification of peptides and proteins
We discuss the characteristics of flow chemistry and how they are applied to various aspects of peptide chemistry
Summary
Proteins, and derivatives thereof can be used as therapeutics and provide tools to investigate biological mechanisms at the molecular level, and their efficient production is of key interest for academia and the pharmaceutical industry. Peptides longer than 50 amino acids are difficult to synthesize due to sequence-dependent aggregation on resin and statistical accumulation of by-products.[6] In contrast to traditional synthesis methods, flow-based SPPS offers high control over reaction conditions, and in-line analysis gives valuable information on individual coupling and deprotection steps. Using this optimized general synthesis recipe, long peptides of up to 164 amino acids were successfully produced at a rate of 25 couplings per hour To validate this approach, the structure and activity of the folded synthetic proteins were compared to the respective recombinantly-expressed proteins. The sequence-dependence of peptide and protein synthesis was investigated by Pentelute, GómezBombarelli and coworkers using the time-dependent UV-traces from AFPS platforms.[14] For this approach, the in-line UV-traces of 35427 Fmoc-removal steps were analyzed to evaluate amino acid-specific coupling efficiencies. Advances in water-compatible protecting groups and activators have recently been reported,[20,21] and warrant investigation in flow-SPPS
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