Recent Advances in Chemical Protein Modification via Cysteine

doi:10.6023/cjoc202203008

Abstract

Proteins are the most abundant biomolecules in nature and are involved almost in all living processes. Chemical modification of proteins is an efficient strategy to mediate and study the physical and chemical properties and biological functionalities of proteins. Most protein chemical modifications are based on the bioorthogonal reactivities of the side chain functional groups of certain amino acid residues. Among 20 proteinogenic amino acids, cysteine has become the best choice for chemical protein modification, owning to its relative low abundance in proteins, the unique nucleophilicity and low redox potential of its mercaptan group. The recent advances in chemical protein modification via cysteine are comprehensively reviewed and the challenges and applications for future development are discussed.

Key words: peptide modification, chemical protein modification, cysteine

Cite this article

Changliu Wang, Yongli Zhao, Junfeng Zhao. Recent Advances in Chemical Protein Modification via Cysteine[J]. Chinese Journal of Organic Chemistry, 2022, 42(9): 2774-2792.

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Fig. & Tab. 43

Scheme 1. Chemical protein modification via cysteine

Scheme 2. Protein modification using iodoacetamide

Scheme 3. Protein Suzuki-Miyaura cross-coupling in aqueous media

Scheme 4. SNAr reactions between perfluoroaromatic molecules and cysteine residues in proteins

Scheme 5. Fluorobenzene reagents for cysteine-selective protein modification

Scheme 6. Cysteine-aminoethylation assisted chemical ubiquitination

Scheme 7. Clinically-approved ADCs with maleimide as the linker

Scheme 8. Ring opening of maleimide-thiol conjugates and thiol-exchange

Scheme 9. Maleimide-thiol adducts stabilized through stretching

Scheme 10. Irreversible modification of polypeptide and protein Cys using carbonylacrylic reagents

Scheme 11. 2-Azoacrylates as bifunctional reagents for peptide and protein Cys modification

Scheme 12. 5-Methylene pyrrolidone as a highly selective and traceless protein Cys modification reagent

Scheme 13. 3-Bromo-5-methylene pyrrolones as cysteine-specific protein multi-functionalization and disulfide rebridging

Scheme 14. 4-Substituted cyclopentenone as a highly active and traceless protein thiol modification reagent

Scheme 15. N-Methyl-N-phenylvinylsulfonamides for cysteine-selective conjugation

Scheme 16. Dinitroimidazoles as bifunctional bioconjugation reagents for protein modification and peptide macrocyclization

Scheme 17. Alkynye containing hypervalent iodine-mediated peptide and protein functionalization

Scheme 18. Site-selective cysteine-cyclooctyne conjugation

Scheme 19. Protein cysteine modification by electrophilic alkynylation using 5-(alkynyl)dibenzothiophenium triflates

Scheme 20. Electron-deficient alkynes as cleavable reagents for protein cysteine modification

Scheme 21. Quaternization of vinyl/alkynyl pyridine for the modification of cysteine-containing peptides

Scheme 22. Application of ethynyl phosphonamidate and diethynyl phosphinates for peptide and protein functionalization

Scheme 23. Allenamides as selective reagents for peptide and protein cysteine modification

Scheme 24. Ynamide as high cysteine-selective modification reagent

Scheme 25. Rhodium-catalyzed cysteine modification with diazo reagents

Scheme 26. Palladium reagents for peptide and protein cysteine modification

Scheme 27. Arylation of peptides and protein cysteine with organometallic gold reagents

Scheme 28. Site-selective protein acetylation

Scheme 29. Selective and reversible photochemical derivatization of cysteine residues in peptides and proteins

Scheme 30. Application of thio-yne reaction in stapled peptide synthesis

Scheme 31. Visible light mediated thiol-ene reactions catalyzed by organic photoredox catalysis

Scheme 32. Cysteine arylation using dual nickel-ruthenium catalysis

Scheme 33. Ligand directed modification of cysteine at the protein level

Scheme 34. Common methods for disulfide formation

Scheme 35. 2-FPBA as selective N-terminal cysteine modification reagent

Scheme 36. TAMM as N-terminal Cys modification reagent

Scheme 37. BAA as N-terminal Cys modification reagent

Scheme 38. Copper-mediated modification of selenocysteines in peptides and proteins

Scheme 39. 18F-Trifluoromethylation of peptides

Scheme 40. Cys-selective modification of peptides and proteins using isoxazoliniums

Scheme 41. Nonenzymatic stereoselective S-glycosylation of peptides and proteins

Scheme 42. Chemoselective labeling of thiols with methylsulfonylphenyloxadiazole reagents

Scheme 43. Synthesis of selenenylsulfide-linked homogeneous glycopeptides and glycoproteins

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