Backbone Protecting Groups for Enhanced Peptide and Protein Synthesis

This review provides a comprehensive account of the use of backbone N-protecting groups in peptide synthesis. It includes detailed synthetic methods relating to their introduction and removal and their application to “difficult” peptides and proteins of biological significance in both academic and industry contexts.
Abstract
Solid-phase peptide synthesis has become an indispensable technique for the routine preparation of linear peptides of up to approximately 40 amino acids in length. However, the solid-phase approach is still hampered by chain insolubility and aggregation, which reduces synthetic yields. Moreover, many of the deletion impurities that can form are often chromatographically inseparable from the target sequence, which diminishes final product purity. The use of backbone N-protecting groups can ameliorate this synthetic inefficiency by increasing peptide chain solubility and suppressing aggregation. Backbone protection is also useful for promoting peptide macrocyclization, suppressing common side reactions in peptide chemistry, and improving solution-phase handling. Commercially available precursors containing benzyl-based groups and pseudoprolines have found widespread use, in academic laboratories and industry. A range of other strategies have also been investigated in a bid to increase the utility of backbone protecting groups and to develop more efficient methods for their introduction and removal. This review provides a comprehensive account of the state of the art, and includes detailed synthetic methods relating to the use of backbone protection, and its application to “difficult” peptides and proteins of biological significance. The strengths and weaknesses of each approach are analyzed, and a commentary on future directions is provided.
Read the complete online review in Angewandte Chemie International Edition
Angew. Chem. Int. Ed. 2025, 64, e202509939
doi.org/10.1002/anie.202509939
Authors: Samuel J. Paravizzini, Dr. Linda M. Haugaard-Kedström, Prof. Craig A. Hutton Dr. John A. Karas
First published: 08 July 2025
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Dr Linda M. Haugaard-Kedström, Director QC & Development PolyPeptide Group |