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Progress in Chemistry 2023, Vol. 35 Issue (4): 526-542 DOI: 10.7536/PC220930 Previous Articles   Next Articles

• Review •

Chemical Synthesis of Peptides and Proteins

Xinyue Wang, Kang Jin()   

  1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Cheeloo College of Medicine, Shandong University,Jinan 250012, China
  • Received: Revised: Online: Published:
  • Contact: *e-mail: jinkang@sdu.edu.cn
  • Supported by:
    Taishan Scholar Program in Shandong Province, the National Natural Science Foundation of China(22007059); Shandong Provincial Key Research and Development Program (Major Technological Innovation Project)(2021CXGC010501)
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As the material basis of active substances and life activities in living organisms, peptides and proteins play vital roles in basic physiological processes such as signal transmission, energy utilization, immune response, etc. And they are closely related to the occurrence of a variety of diseases. An important prerequisite for studying their structure and biological function and developing related drugs is to obtain a certain number of high pure peptides and proteins. The sources of natural peptides and proteins mainly include tissues and organs of animals and plants, secondary metabolites of microorganisms, etc. Natural extraction, recombinant technology, and chemical synthesis are the main methods to obtain peptides and proteins. Chemical synthesis can conveniently introduce unnatural amino acids or specific types of post-translational modification groups at any site of peptides and proteins compared with the former two, such as glycosylation, phosphorylation, fluorophores, and photorelinking reaction groups, which has greatly promoted the application and development of peptides and proteins in the field of medicine research. This review comprehensively introduces the various chemical synthesis strategies of peptides and proteins, along with the basic principles, advantages and disadvantages, and application values, aiming to provide a novel sight for synthesizing peptides and proteins.

Key words: peptide synthesis, difficult peptides, protein synthesis, chemical strategies
Fig.1 Basic procedures of Solid phase peptide synthesis
Table 1 Common resins used in Fmoc-SPPS
Name Structure ref
Wang resin 21
2-Chlorotrityl
Chloride resin
(2-Cl-(Trt)-Cl resin)		 22
2-Cl-(Trt)-
NHNH2
Fmoc resin		 23
BAL resin 24
MeDbz-resin 25
Rink Amide
resin		 26
ChemMatrix
resin		 27
Table 2 Common coupling reagents
Type Name Structure ref
carbodiimides DCC 28
DIC 29
EDC 30
Oxyma 31
phosphonium
salts		 PyBop 32
PyAop 33
PyOxim 34
Uronium/
aminium
salts		 HBTU 35
HATU 35
HAPy-U 36
COMU 37
Fig.2 Hydrogen bonds contribute to aggregates of peptide
Table 3 Application scopes and advantages of difficult peptides synthesis strategies
Synthesis
strategies		 Application scopes Advantages
Pseudo-Prolines Difficult peptides, cyclization of peptides Disrupting the formation of hydrogen bond; Inducing cis-amide conformation
ortho-Hydroxybenzyl structure Difficult peptides Disrupting the formation of hydrogen bond
O-acyl isopeptide Difficult peptides Preventing β-sheet interactions and subsequent aggregations;Stable in TFA condition
Pegylation Difficult peptides,non-
polar peptides		 Solubilization
Fig.3 (a)Pseudoproline removed conveniently during acidic global deprotection of peptides; (b)Normal trans-amide and cis-amide caused by pseudoproline, and the latter is preferred during cyclization of cyclic Peptides
Fig.4 (a) Mechanism of next amino acid introduction into N(Hmb)-peptidyl-resin; (b) Hmsb and Hmnb
Fig.5 (a) Synthesis of isopeptide using dipeptide unit; Mechanism of isopeptide to peptide through O/N acyl shift mediated by (b): pH and (c): photoirradiation[57]
Fig.6 Amino acids linked with PEG group
Fig.7 On-resin cyclization using the MeDbz Linker[67]
Table 4 Application scopes and advantages of peptide ligation methods
Peptide ligation methods Application scopes Advantages
NCL N-terminal residue is cysteine or thiol-derived amino acid Mild, aqueous conditions
Useing completely
unprotected peptide
fragments
DSL N-terminal residue is selenocystine diselenide Faster than NCL
STL N-terminal residue is
Ser or Thr		 Compatibility with most of the C-terminal residues except Asp, Glu, and Lys
Simple operation in pyridine/AcOH solution
CPL N-terminal residue is cysteine or Penicillamine Compatibility with sterically demanding amino acids at the C-terminus
KAHA ligation Ligation junctions such as Phe-Ala, Ala-Phe, Pro-Ala, and Ala-Ala
are viable		 Producing only
H2O and CO2 as
by-products
Without
additional reagents
Fig.8 Mechanism of NCL
Fig.9 (a) Peptide hydrazide serves as thioester surrogate used in NCL[72]; (b) peptide hydrazide synthesis on 2-Cl-(Trt)-NHNH2 resin[73]; (c) generation of peptide thioester surrogate: acyl pyrazoles[72]
Fig.10 Synthesis of peptide crypto-thioesters: N-Hnb-Cys(StBu) and its Mechanism for transformation to peptide thioester during NCL[75]
Fig.11 (a) Using thiol-derived amino acids in NCL and further desulfurization[79]; (b) γ-thiol Ile, β-thiol Lys and γ-thiol Pro
Fig.12 Steps of DSL[18]
Fig.13 Mechanism of Ser/Thr ligation
Fig.14 (a) Synthesis of SAL ester by “n+1” strategy; (b) High hindrance of terminal AA contributes to the deactivation roles of the α-N-carbonyl in a peptidyl prolylester; (c) steps of CPL[93]
Fig.15 KAHA ligation: peptides ligate between an N-terminal peptide α-ketoacid and a C-terminal peptide hydroxylamine
Fig.16 (a) Poly-arginine tag and Poly-lysine tag; (b) synthesis of membrane proteins through a removable backbone modification-RBM Tag[103]; (c) membrane protein synthesis via reducible solubilizing tags (RSTs)[90]
Fig.17 Steps of Sortase-mediated protein Semisynthesis
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