Advances in the chemical synthesis of human proteoforms

Access to structurally-defined human proteoforms is essential to the biochemical studies on human health and medicine. Chemical protein synthesis provides a bottom-up and atomic-resolution approach for the preparation of homogeneous proteoforms bearing any number of post-translational modifications of any structure, at any position, and in any combination. In this review, we summarize the development of chemical protein synthesis, focusing on the recent advances in synthetic methods, product characterizations, and biomedical applications. By analyzing the chemical protein synthesis studies on human proteoforms reported to date, this review demonstrates the significant methodological improvements that have taken place in the field of human proteoform synthesis, especially in the last decade. Our analysis shows that although further method development is needed, all the human proteoforms could be within reach in a cost-effective manner through a divide-and-conquer chemical protein synthesis strategy. The synthetic proteoforms have been increasingly used to support biomedical research, including spatial-temporal studies and interaction network analysis, activity quantification and mechanism elucidation, and the development and evaluation of diagnostics and therapeutics.