Chemical Synthesis of Proteins Containing 300 Amino Acids
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doi: 10.1007/s40242-020-0150-y
Review
Chemical Synthesis of Proteins Containing 300 Amino Acids ZHANG Baochang, LI Yulei, SHI Weiwei, WANG Tongyue, ZHANG Feng and LIU Lei* Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology(Ministry of Education), Center for Synthetic and Systems Biology, State Key Laboratory of Chemical Oncogenomics(Shenzhen), Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China Abstract Chemical synthesis of proteins containing up to 300 amino acids may cover 30%―50% of all the proteins encountered in biomedical studies and may provide an alternate approach to the usually used recombinant expression technology, vastly expanding the chemical space of the latter. In the present review article, we tried to survey the recent progresses made for more rapid synthesis of increasingly long peptides and more efficient ligation of multiple peptide segments. The developments of seminal methods by many research groups have greatly contributed to the recent breakthroughs in the successful total synthesis of a number of functionally important proteins , such as oligoubiquitins, bacterial GroEL/ES chaperones, and mirror-image DNA polymerases. Through these studies, a potential bottleneck has also been recognized for the chemical synthesis of large proteins, namely, how to ensure that each peptide segment from a large protein avoids unfavorable aggregation when dissolved in aqueous solution. Many new methods, such as removable backbone modification(RBM) strategy have been developed to overcome this bottleneck, while more studies need to be carried out to develop more effective and less costly methods that ultimately, may lead to fully automatable chemical synthesis of customized proteins of 300 amino acids bearing any artificial designs. Keywords Chemical protein synthesis; Solid-phase synthesis; Peptide; Ligation; 300 amino acid
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Introduction
Proteins play central roles in all the biochemical processes and biomedical applications[1]. An important task of biomedical research is to elucidate the biochemical and structural mechanisms behind protein functions and to develop various types of protein-based functional molecules. Under normal circumstances, the method of biological expression is used to obtain the proteins[2]. However, there are sometimes challenges in using the recombinant method to obtain certain families of proteins, such as post-translationally modified proteins and man-made proteins with unnatural structural motifs[3]. To overcome this problem, many researchers have been working on chemical protein synthesis, which in theory can be used to obtain any proteins with precisely designed structures at high flexibility. For instance, post-translationally modified proteins bearing ubiquitination and phosphorylation can be chemically synthesized and used for structural and biochemical studies[4]. PEGylated and glycosylated protein drugs can be chemically synthesized to improve their bioavailability and metabolic stabil
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