Yang Ziyi, Xiao Yudi, Shi Yang, Liu Lei
New Cornerstone Science Laboratory, Tsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, 100084, China.
Sci China Life Sci. 2025 Apr 8. doi: 10.1007/s11427-024-2860-5.
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.
获取结构明确的人类蛋白质异构体对于人类健康和医学的生化研究至关重要。化学蛋白质合成提供了一种自下而上且具有原子分辨率的方法，用于制备具有任意数量、任意结构、位于任意位置且以任意组合形式存在的翻译后修饰的均一蛋白质异构体。在本综述中，我们总结了化学蛋白质合成的发展，重点关注合成方法、产物表征及生物医学应用方面的最新进展。通过分析迄今为止报道的关于人类蛋白质异构体的化学蛋白质合成研究，本综述展示了人类蛋白质异构体合成领域所取得的重大方法学改进，尤其是在过去十年中。我们的分析表明，尽管仍需进一步开发方法，但通过分而治之的化学蛋白质合成策略，所有人类蛋白质异构体都有望以具有成本效益的方式得以实现。合成的蛋白质异构体已越来越多地用于支持生物医学研究，包括时空研究和相互作用网络分析、活性定量和机制阐明，以及诊断和治疗方法的开发与评估。
